Combination therapy employing ileal bile acid transport inhibiting benzothiepiens and HMG Co-A reductase inhibitors

ABSTRACT

Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also provided are compositions and methods for combination therapy employing ileal bile acid transport inhibitors and HMG Co-A reductase inhibitors for the treatment of hyperlipidemic conditions.

[0001] This application claims the benefit of priority of U.S.provisional application Serial No. 60/040,660, filed Mar. 11, 1997. Thisapplication is also a continuation-in-part application of U.S. Ser. No.08/831,284, filed Mar. 31, 1997, which is a continuation application ofU.S. Ser. No. 08/517,051, filed Aug. 21, 1995, which is acontinuation-in-part application of U.S. Ser. No. 08/305,526 filed Sep.12, 1994; and is a continuation-in-part application of U.S. Ser. No.08/816,065, filed Mar. 11, 1997, which claims priority from U.S.provisional application Serial No. 60/013,119, filed Mar. 11, 1996.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to novel benzothiepines,derivatives and analogs thereof, in combination with HMG Co-A reductaseinhibitors, pharmaceutical compositions containing them, and use ofthese compositions in medicine, particularly in the prophylaxis andtreatment of hyperlipidemic conditions such as is associated withatherosclerosis or hypercholesterolemia, in mammals.

[0004] 2. Description of Related Art

[0005] It is well-settled that hyperlipidemic conditions associated withelevated concentrations of total cholesterol and low-density lipoproteincholesterol are major risk factors for coronary heart disease andparticularly atherosclerosis. Interfering with the circulation of bileacids within the lumen of the intestinal tract is found to reduce thelevels of serum cholesterol in a causal relationship. Epidemiologicaldata has accumulated which indicates such reduction leads to animprovement in the disease state of atherosclerosis. Stedronsky, in“Interaction of bile acids and cholesterol with nonsystemic agentshaving hypocholesterolemic properties,” Biochimica et Biophysica Acta,1210 (1994) 255-287 discusses the biochemistry, physiology and knownactive agents surrounding bile acids and cholesterol.

[0006] Pathophysiologic alterations are shown to be consistent withinterruption of the enterohepatic circulation of bile acids in humans byHeubi, J. E., et al. See “Primary Bile Acid Malabsorption: Defective inVitro Ileal Active Bile Acid Transport”, Gastroenterology,1982:83:804-11.

[0007] In fact, cholestyramine binds the bile acids in the intestinaltract, thereby interfering with their normal enterohepatic circulation(Reihnér, E., et al, in “Regulation of hepatic cholesterol metabolism inhumans: stimulatory effects of cholestyramine on HMG-CoA reductaseactivity and low density lipoprotein receptor expression in gallstonepatients”, Journal of Lipid Research, Volume 31, 1990, 2219-2226 andSuckling el al, “Cholesterol Lowering and bile acid excretion in thehamster with cholestyramine treatment”, Atherosclerosis, 89(1991)183-190). This results in an increase in liver bile acid synthesis bythe liver using cholesterol as well as an upregulation of the liver LDLreceptors which enhances clearance of cholesterol and decreases serumLDL cholesterol levels.

[0008] In another approach to the reduction of recirculation of bileacids, the ileal bile acid transport system is a putative pharmaceuticaltarget for the treatment of hypercholesterolemia based on aninterruption of the enterohepatic circulation with specific transportinhibitors (Kramer, et al, “Intestinal Bile Acid Absorption” The Journalof Biological Chemistry, Vol. 268, No. 24, Issue of August 25, pp.18035-18046, 1993).

[0009] In a series of patent applications, eg Canadian PatentApplication Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EPApplication Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, HoechstAktiengesellschaft discloses polymers of various naturally occurringconstituents of the enterohepatic circulation system and theirderivatives, including bile acid, which inhibit the physiological bileacid transport with the goal of reducing the LDL cholesterol levelsufficiently to be effective as pharmaceuticals and; in particular foruse as hypocholesterolemic agents.

[0010] In vitro bile acid transportinhibition is disclosed to showhypolipidemic activity in The Wellcome Foundation Limited disclosure ofthe world patent application No. WO 93/16055 for “HypolipidemicBenzothiazepine Compounds”

[0011] Selected benzothiepines are disclosed in world patent applicationNo. WO93/321146 for numerous uses including fatty acid metabolism andcoronary vascular diseases.

[0012] Other selected benzothiepines are known for use as hypolipaemicand hypocholesterolaemic agents, especially for the treatment orprevention of atherosclerosis as disclosed by application Nos. EP508425, FR 2661676, and WO 92/18462, each of which is limited by anamide bonded to the carbon adjacent the phenyl ring of the fused bicyclobenzothiepine ring.

[0013] The above references show continuing efforts to find sale,effective agents for the prophylaxis and treatment of hyperlipidemicdiseases and their usefulness as hypocholesterolemic agents.

[0014] Additionally selected benzothiepines are disclosed for use invarious disease states not within the present invention utility. Theseare EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. Pat. No.3,520,891 abstracted in Derwent 50701R-B; U.S. Pat. No. 3,287,370, U.S.Pat. No. 3,389,144; U.S. Pat. No. 3,694,446 abstracted in Derwent Abstr.No. 65860T-B and WO 92/18462.

[0015] HMG Co-A reductase inhibitors have been used ascholesterol-lowering agents. This class of compounds inhibits3-hydroxy-3-methylglutaryl-coenzyme A (HMG Co-A) reductase. This enzymecatalyzes the conversion of HMG Co-A to mevalonate, which is an earlyand rate-limiting step in the biosythesis of cholesterol.

[0016] Benzothiazepine anti-hyperlipidemic agents are disclosed in WO94/18183, WO 94/18184, WO 96/05188, WO 96/16051, AU-A-30209/92,AU-A-61946/94, AU-A-61948/94, and AU-A-61949/94.

[0017] The present invention furthers such efforts by providing novelpharmaceutical compositions and methods for treatment of hyperlipidemicconditions.

SUMMARY OF THE INVENTION

[0018] Accordingly, among its various aspects, the present inventionprovides compounds of formula (I):

[0019] wherein:

[0020] q is an integer from 1 to 4;

[0021] n is an integer from 0 to 2;

[0022] R¹ and R² are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

[0023] wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl,alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, andcycloalkyl optionally are substituted with one or more substituentsselected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹,S⁺R⁹R¹⁰A-, P⁺,R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo,and CONR⁹R¹⁰,

[0024] wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, P⁺R⁹R¹⁰A-, orphenylene,

[0025] wherein R⁹, R¹⁰, and R^(w) are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, andarylalkyl; or

[0026] R¹ and R² taken together with the carbon to which they areattached form C₃-C₁₀ cycloalkylidene;

[0027] R³ and R⁴ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle OR⁹, NR⁹R¹⁰, SR⁹,S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or

[0028] R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or═CR¹¹R¹²,

[0029] wherein R¹¹ and R¹² are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH₂ and SH, or

[0030] R¹¹ and R¹² together with the nitrogen or carbon atom to whichthey are attached form a cyclic ring;

[0031] R⁵ and R⁶ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, quaternary heteroaryl, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,

[0032] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,quaternary heterocycle, and quaternary heteroaryl can be substitutedwith one or more substituent groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, heteroaryl arylalkyl, quaternaryheterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, N¹³R¹⁴, SR¹³,S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A-, P(OR¹³)OR¹⁴, SR⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0033] wherein:

[0034] A⁻ A is a pharmaceutically acceptable anion and M is apharmaceutically acceptable cation,

[0035] said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle and heteroar can be furthersubstituted with one or more substituent groups selected from the groupconsisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo,CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and

[0036] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally haveone or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-,PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, and R¹³, R¹⁴, and R¹⁵ areindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle,heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternaryheteroarylalkyl,

[0037] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, andpolyalkyl optionally have one or more carbons replaced by O, NR⁹,N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene,carbohydrate, amino acid, peptide, or polypeptide, and

[0038] R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or moregroups selected from the group consisting of sulfoalkyl, quaternaryheterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹,S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM,SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, and C(O)OM,

[0039] wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or

[0040] R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring;

[0041] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen and alkyl; and

[0042] one or more R^(x) are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl,arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl,polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴,SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴,NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴,N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, andcarbohydrate,

[0043] wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl,heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternaryheterocycle, and quaternary heteroaryl can be further substituted withOR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻,S⁺R⁹R¹⁰A⁻, or C(O)OM, and

[0044] wherein R¹⁸ is selected from the group consisting of acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl

[0045] wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,heteroaryl, alkyl quaternary heterocycle, and quaternary heteroaryloptionally are substituted with one or more substituents selected fromthe group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂R⁹R¹⁰,PO(OR¹⁶)OR¹⁷, and C(O)OM,

[0046] wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A-, PR¹³, P(O)R¹³ P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl,

[0047] wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹;

[0048] wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A-, P(OR¹³)OR¹⁴, S⁻R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0049] provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH andwhen R⁵ is OH, R¹, R², R³, R⁴, R⁷ and R⁸ cannot be all hydrogen;

[0050] provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H;

[0051] provided that when q=1 and R^(x) is styryl, anilido, oranilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or

[0052] a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0053] Preferably, R⁵ and R⁶ can independently be selected from thegroup consisting of H, aryl, heterocycle, quaternary heterocycle, andquaternary heteroaryl,

[0054] wherein said aryl, heterocycle, heteoaryl, quaternaryheterocycle, and quaternary heteroaryl can be substituted with one ormore substituent groups independently selected from the group consistingof alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A-, P(OR¹³)OR¹⁴, S+R¹³R¹⁴A-, and N⁺R⁹R¹¹R¹²A-,

[0055] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally haveone or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-,PR⁷, P(O)R⁷ P⁺R⁷R⁸A-, or phenylene,

[0056] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle and heteroaryl can be furthersubstituted with one or more substituent groups selected from the groupconsisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo,CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P³⁰ R⁷R⁸R⁹A-, and P(O)(OR⁷)OR⁸.

[0057] More preferably, R⁵ or R⁶ has the formula:

—Ar—(R^(y))_(t)

[0058] wherein:

[0059] t is an integer from 0 to 5;

[0060] Ar is selected from the group consisting of phenyl, thiophenyl,pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl,anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl,isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl,and benzoisothiazolyl; and

[0061] one or more R^(y) are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl OR⁹, SR⁹,S(O)R⁹, SO₂R⁹, and SO₃R⁹,

[0062] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,and heteroaryl can be substituted with one or more substituent groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A-,P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0063] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, and heteroaryl can be furthersubstituted with one or more substituent groups selected from the groupconsisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo,CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, P(O)PR⁷R⁸, P⁺R⁷R⁸R⁹A-, and P(O) (OR⁷)OR⁸, and

[0064] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, and heteroaryl can optionally haveone or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-,PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene.

[0065] Most preferably, R⁵ or R⁶ has the formula (II):

[0066] The invention is further directed to a compound selected fromamong:

R²⁰-R¹⁹-R²¹   (Formula DI)

[0067]

[0068] wherein R¹⁹ is selected from the group consisting of alkane diyl,alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl,polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide,wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxydiyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,peptide, and polypeptide can optionally have one or more carbon atomsreplaced by O, NR⁷, N⁺R⁷R⁸, S, SO, SO₂, S⁺R⁷R⁸, PR⁷, P⁺P⁷R⁸, phenylene,heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl,or aryl,

[0069] wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl,alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,peptide, and polypeptide can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, SO₂R¹³, SO₂R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)N¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A-,P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;

[0070] wherein R¹⁹ further comprises functional linkages by which R¹⁹ isbonded to R²⁰, R²¹, or R²² in the compounds of Formulae DII and DIII,and R²³ in the compounds of Formula DIII. Each of R²⁰, R²¹, or R²² andR²³ comprises a benzothiepine moiety as described above that istherapeutically effective in inhibiting ileal bile acid transport.

[0071] The invention is also directed to a compound selected from amongFormula DI, Formula DII and Formula DIII in which each of R²⁰, R²¹, R²²and R²³ comprises a benzothiepine moiety corresponding to the Formula:

[0072] wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(x), and n are asdefined in Formula I as described above, and R⁵⁵ is either a covalentbond or arylene.

[0073] In compounds of Formula DIV, it is particularly preferred thateach of R²⁰, R²¹, and R²² in Formulae DII and DIII, and R²³ in FormulaDIII, be bonded at its 7- or 8-position to R¹⁹. In compounds of FormulaDIVA, it is particularly preferred that R⁵⁵ comprise a phenylene moietybonded at a m- or p-carbon thereof to R¹⁹.

[0074] Examples of formula DI include:

[0075] In any of the dimeric or multimeric structures discussedimmediately above, benzothiepine compounds of the present invention canbe used alone or in various combinations.

[0076] In any of the compounds of the present invention, R¹ and R² canbe ethyl/butyl or butyl/butyl.

[0077] Other compounds useful in the present invention as ileal bileacid transport inhibitors are shown in Appendix A.

[0078] In another aspect, the present invention provides apharmaceutical composition for the prophylaxis or treatment of a diseaseor condition for which a bile acid transport inhibitor is indicated,such as a hyperlipidemic condition, for example, atherosclerosis. Suchcompositions comprise any of the compounds disclosed above, alone or incombination, in an amount effective to reduce bile acid levels in theblood, or to reduce transport thereof across digestive system,membranes, and a pharmaceutically acceptable carrier, excipient, ordiluent.

[0079] In a further aspect, the present invention also provides a methodof treating a disease or condition in mammals, including humans, forwhich a bile acid transport inhibitor is indicated, comprisingadministering to a patient in need thereof a compound of the presentinvention in an effective amount in unit dosage form or in divideddoses.

[0080] In yet a further aspect, the present invention also providesprocesses for the preparation of compounds of the present invention.

[0081] In yet another aspect, the present invention provides acombination therapy comprising the use of a first amount of an ilealbile acid transport inhibitor and a second amount of a HMG Co-Areductase inhibitor useful to treat hyperlipidemic disorders, whereinsaid first and second amounts together comprise an anti-hyperlipidemiccondition effective amount of said compounds.

[0082] HMG Co-A reductase inhibitor compounds useful in the presentinvention are shown in Appendix B.

[0083] Further scope of the applicability of the present invention willbecome apparent from the detailed description provided below. However,it should be understood that the following detailed description andexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0084] The following detailed description is provided to aid thoseskilled in the art in practicing the present invention. Even so, thisdetailed description should not be construed to unduly limit the presentinvention as modifications and variations in the embodiments discussedherein can be made by those of ordinary skill in the art withoutdeparting from the spirit or scope of the present inventive discovery.

[0085] The contents of each of the references cited herein, includingthe contents of the references cited within these primary references,are herein incorporated by reference in their entirety.

[0086] Definitions

[0087] In order to aid the reader in understanding the followingdetailed description, the following definitions are provided:

[0088] “Alkyl”, “alkenyl,” and “alkynyl” unless otherwise noted are eachstraight chain or branched chain hydrocarbons of from one to twentycarbons for alkyl or two to twenty carbons for alkenyl and alkynyl inthe present invention and therefore mean, for example, methyl, ethyl,propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl,or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynylrespectively and isomers thereof.

[0089] “Aryl” means a fully unsaturated mono- or multi-ring carbocyle,including, but not limited to, substituted or unsubstituted phenyl,naphthyl, or anthracenyl.

[0090] “Heterocycle” means a saturated or unsaturated mono- ormulti-ring carbocycle wherein one or more carbon atoms can be replacedby N, S, P, or O. This includes, for example, the following structures:

[0091] wherein Z, Z′, Z″ or Z″′ is C, S, P, O, or N, with the provisothat one of Z, Z′, Z″ or Z″′ is other than carbon, but is not O or Swhen attached to another Z atom by a double bond or when attached toanother O or S atom. Furthermore, the optional substituents areunderstood to be attached to Z, Z′, Z″ or Z″′ only when each is C.

[0092] The term “heteroaryl” means a fully unsaturated heterocycle.

[0093] In either “heterocycle” or “heteroaryl,” the point of attachmentto the molecule of interest can be at the heteroatom or elsewhere withinthe ring.

[0094] The term “quaternary heterocycle” means a heterocycle in whichone or more of the heteroatoms, for example, O, N, S, or P, has such anumber of bonds that it is positively charged. The point of attachmentof the quaternary heterocycle to the molecule of interest can be at aheteroatom or elsewhere.

[0095] The term “quaternary heteroaryl” means a heteroaryl in which oneor more of the heteroatoms, for example, O, N, S, or P, has such anumber of bonds that it is positively charged. The point of attachmentof the quaternary heteryaryl to the molecule of interest can be at aheteroatom or elsewhere.

[0096] The term “halogen” means a fluoro, chloro, bromo or iodo group.

[0097] The term “haloalkyl” means alkyl substituted with one or morehalogens.

[0098] The term “cycloalkyl” means a mono- or multi-ringed carbocyclewherein each ring contains three to ten carbon atoms, and wherein anyring can contain one or more double or triple bonds.

[0099] The term “diyl” means a diradical moiety wherein said moiety hastwo points of attachment to molecules of interest.

[0100] The term “oxo” means a doubly bonded oxygen.

[0101] The term “polyalkyl” means a branched or straight hydrocarbonchain having a molecular weight up to about 20,000, more preferably upto about 10,000, most preferably up to about 5,000.

[0102] The term “polyether” means a polyalkyl wherein one or morecarbons are replaced by oxygen, wherein the polyether has a molecularweight up to about 20,000, more preferably up to about 10,000, mostpreferably up to about 5,000.

[0103] The term “polyalkoxy” means a polymer of alkylene oxides, whereinthe polyalkoxy has a molecular weight up to about 20,000, morepreferably up to about 10,000, most preferably up to about 5,000.

[0104] The term “cycloaklylidene” means a mono- or multi-ringedcarbocycle wherein a carbon within the ring structure is doubly bondedto an atom which is not within the ring structures.

[0105] The term “carbohydrate” means a mono-, di-, tri-, orpolysaccharide wherein the polysaccharide can have a molecular weight ofup to about 20,000, for example, hydroxypropyl-methylcellulose orchitosan.

[0106] The term “peptide” means polyamino acid containing up to about100 amino acid units.

[0107] The term “polypeptide” means polyamino acid containing from about100 amino acid units to about 1000 amino acid units, more preferablyfrom about 100 amino acid units to about 750 amino acid untis, mostpreferably from about 100 amino acid units to about 500 amino acidunits.

[0108] The term “alkylammoniumalkyl” means a NH² group or a mono-, di-or tri-substituted amino group, any of which is bonded to an alkylwherein said alkyl is bonded to the molecule of interest.

[0109] The term “triazolyl” includes all positional isomers. In allother heterocycles and heteroaryls which contain more than one ringheteroatom and for which isomers are possible, such isomers are includedin the definition of said heterocycles and heteroaryls.

[0110] The term “sulfoalkyl” means an alkyl group to which a sulfonategroup is bonded, wherein said alkyl is bonded to the molecule ofinterest.

[0111] The term “active compounds” means a compound of the presentinvention which inhibits transport of bile acids.

[0112] When used in combination, for example “alkylaryl” or “arylalkyl,”the individual terms listed above have the meaning indicated above.

[0113] The term “a bile acid transport inhibitor” means a compoundcapable of inhibiting absorption of bile acids from the intestine intothe circulatory system of a mammal, such as a human. This includesincreasing the fecal excretion of bile acids, as well as reducing theblood plasma or serum concentrations of cholesterol and cholesterolester, and more specifically, reducing LDL and VLDL cholesterol.Conditions or diseases which benefit from the prophylaxis or treatmentby bile acid transport inhibition include, for example, a hyperlipidemiccondition such as atherosclerosis.

[0114] The phrase “combination therapy” refers to the administration ofan ileal bile acid transport inhibitor and a HMG Co-A reductaseinhibitor to treat a hyperlipidemic condition, for exampleatherosclerosis and hypercholesterolemia. Such administrationencompasses co-administration of these inhibitors in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each inhibitoragent. In addition, such administration also encompasses use of eachtype of inhibitor in a sequential manner. In either case, the treatmentregimen will provide beneficial effects of the drug combination intreating the hyperlipidemic condition.

[0115] The phrase “theraputically effective” is intended to qualify thecombined amount of inhibitors in the combination therapy. This combinedamount will achieve the goal of reducing or eliminating thehyperlipidemic condition.

[0116] Compounds

[0117] The compounds of the present invention can have at least twoasymmetrical carbon atoms, and therefore include racemates andstereoisomers, such as diastereomers and enantiomers, in both pure formand in admixture. Such stereoisomers can be prepared using conventionaltechniques, either by reacting enantiomeric starting materials, or byseparating isomers of compounds of the present invention.

[0118] Isomers may include geometric isomers, for example cis isomers ortrans isomers across a double bond. All such isomers are contemplatedamong the compounds of the present invention.

[0119] The compounds of the present invention also include tautomers.

[0120] The compounds of the present invention as discussed below includetheir salts, solvates and prodrugs.

[0121] Compound Syntheses

[0122] The starting materials for use in the preparation of thecompounds of the invention are known or can be prepared by conventionalmethods known to a skilled person or in an analogous manner to processesdescribed in the art.

[0123] Generally, the compounds of the present invention can be preparedby the procedures described below.

[0124] For example, as shown in Scheme I, reaction of aldehyde II withformaldehyde and sodium hydroxide yields the hydroxyaldehyde III whichis converted to mesylate IV with methanesulfonyl chloride andtriethylamine similar to the procedure described in Chem. Ber. 98,728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared bythe procedure described in WO 93/16055, in the presence of triethylamineyields keto-aldehyde VI which can be cyclized with the reagent, preparedfrom zinc and titanium trichloride in refluxing ethylene glycol dimethylether (DME), to give a mixture of 2,3-dihydrobenzothieoine VII and tworacemic steroisomers of benzothiepin-(5H)-4-one VIII when R¹ and R² arenonequivalent. Oxidation of VII with 3 equivalents ofm-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IXwhich upon hydrogenation with palladium on carbon as the catalyst yielda mixture of four racemic stereoisomers of4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two racemicstereoisomers of 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxides XI whenR¹ and R² are nonequivalent.

[0125] Optically active compounds of the present invention can beprepared by using optically active starting material III or byresolution of compounds X with optical resolution agents well known inthe are as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781(1977), and ibid., 44, 4891 (1979).

[0126] Alternatively, keto-aldehyde VI where R² is H can be prepared byreaction of thiophenol V with a 2-substituted acrolein.

[0127] Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to givethe benzothiepin-(5H)-4-one-1,1-dioxide XII which can be reduced withsodium borohydride to give four racemic stereoisomers of X. The twostereoisomers of X, Xa and Xb, having the OH group and R⁵ on theopposite sides of the benzothiepine ring can be converted to the othertwo isomers of X, Xc and Xd, having the OH group and R⁵ on the safe sideof the benzothiepine ring by reaction in methylene chloride with 40-50%sodium hydroxide in the presence of a phase transfer catalyst (PTC). Thetransformation can also be carried out with potassium t-butoxide in THF.

[0128] The compounds of the present invention where R³ is OR, NRR′ orS(O)_(n)R and R⁴ is hydroxy can be prepared by reaction of epoxide IXwhere R⁵ is H with thiol, alcohol, or amine in the presence of a base.

[0129] Another route to Xc and Xd of the present invention is shown inScheme 2. Compound VI is oxidized to compound XIII with two equivalentof m-chloroperbenzoic acid. Hydrogenolysis of compound XIII withpalladium on carbon yields compound XIV which can be cyclized witheither potassium t-butoxide or sodium hydroxide under phase transferconditions to a mixture of Xc and Xd. Separation of Xc and Xd can beaccomplished by either HPLC or fractional crystallization.

[0130] The thiophenols XVIII and V used in the present invention canalso be prepared according to the Scheme 3. Alkylation of phenol XV withan arylmethyl chloride in a nonpolar solvent according to the procedurein J. Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenolXVI. The phenol XVI can be converted to the thiophenol XVIII via thethiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980(1966). The phenol XVI is first reacted with dimethyl thiocarbamoylchloride and triethylamine to give thiocarbamate XVII which is thermallyrearranged at 200-300° C., and the rearranged product is hydrolyzed withsodium hydroxide to yield the thiophenol XVIII. Similarly, Thiophenol Vcan also be prepared from 2-acylphenol XIX via the intermediatethiocarbanate XX.

[0131] Scheme 4 shows another route to benzothiepine-1,1-dioxides Xc andXd starting from the thiophenol XVIII. Compound XVIII can be reactedwith mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI withtwo equivalents of MCPBA yields the sulfone-aldehyde XIV which can becyclized with potassium t-butoxide to a mixture of Xc and Xd.Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives amixture of benzothiepine XXIIc and XXIId.

[0132] Examples of amine- and hydroxylamine-containing compounds of thepresent invention can be prepared as shown in Scheme 5 and Scheme 6.2-Chloro-5-nitrobenzophenone is reduced with triethylsilane andtrifluoromethane sulfonic acid to 2-chloro-5-nitrodiphenylmethane 32.Reaction of 32 with lithium sulfide followed by reacting the resultingsulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation ofXXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV which canbe reduced by hydrogenation to the hydroxylamine XXV. Protecting thehydroxylamine XXV with di-t-butyldicarbonate gives theN,O-di-(t-butoxycarbonyl)hydroxylamino derivative XXVI. Cyclization ofXXVI with potassium t-butoxide and removal of the t-butoxycarbonylprotecting group gives a mixture of hydroxylamino derivatives XXVIIc andXXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also beprepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

[0133] In Scheme 6, reduction of the sulfone-aldehyde XXV with hydrogenfollowed by reductive alkylation of the resulting amino derivative withhydrogen and an aldehyde catalyzed by palladium on carbon in the samereaction vessel yields the substituted amine derivative

[0134] XXVIII. Cyclization of XXVIII with potassium t-butoxide yields amixture of substituted amino derivatives of this invention XXIXc andXXIXd.

[0135] Scheme 7 describes one of the methods of introducing asubstituent to the aryl ring at the 5-position of benzothiepine.Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercurictriflate gives the iodo derivative XXXI, which upon palladium-catalyzedcarbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis ofthe carboxylate

[0136] and derivatization of the resulting acid to acid derivatives arewell known in the art.

[0137] Abbreviations used in the foregoing description have thefollowing meanings:

[0138] THF—tetrahydrofuran

[0139] PTC—phase transfer catalyst

[0140] Aliquart 336—methyltricaprylylammonium chloride

[0141] MCPBA—m-chloroperbenzoic acid

[0142] Celite—a brand of diatomaceous earth filtering aid

[0143] DMF—dimethylformamide

[0144] DME—ethylene glycol dimethyl ether

[0145] BOC—t-butoxycarbonyl group

[0146] R¹ and R² can be selected from among substituted andunsubstituted C₁ to C₁₀ alkyl wherein the substituent(s) can be selectedfrom among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containingheterocycles joined to the C₁ to C₁₀ alkyl through an ether linkage.Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl, —CH₂C(═O)C₂H₅, —CH₂OC₂H₅, and—CH₂O—(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl arepreferred. In certain particularly preferred compounds of the presentinvention, substituents R¹ and R² are identical, for examplen-butyl/n-butyl, so that the compound is achiral at the 3-carbon.Eliminating optical isomerism at the 3-carbon simplifies the selection,synthesis, separation, and quality control of the compound used as anileal bile acid transport inhibitor. In both compounds having a chiral3-carbon and those having an achiral 3-carbon, substituents (R^(x)) onthe benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo,alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy,(N)-hydroxcarbonylalkyl amine, haloalkylthio, haloalkylsulfinyl,haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino,(N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl,trialkylammonium (especially with a halide counterion), (N)-amido,(N)-alkylamido, —N-alkylamido, —N,N-dialkylamido, (N)-haloalkylamido,(N)-sulfonamido, (N)-alkylsulfonamido, (N)-haloalkylsulfonamido,carboxyalkylamino, trialkyl-ammonium salt, (N)-carbamic acid, alkyl orbenzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate,thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxysubstituent on one or more of the alkyl substituents, an alkylene bridgehaving a quaternary ammonium salt substituted thereon,—[O(CH₂)_(w)]_(x)—X where x is 2 to 12, w is 2 or 3 and X is a halo or aquaternary ammonium salt, and (N)-nitrogen containing heterocyclewherein the nitrogen of said heterocycle is optionally quaternized.Among the preferred species which may constitute R^(x) are methyl,ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy,methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl,ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino,N,N-diethylamino, (N)-benzyloxycarbamoyl, triethylammonium, A⁻,—NHC(═O)CH₃, —NHC(═O)C₄H₁₁, —NHC(═O)C₅H₁₃, carboxyethylamino,(N)-morpholinyl, (N)-azetidinyl, (N)—N-methylazetidinium A⁻,(N)-pyrrolidinyl, pyrrolyl, (N)—N-methylpyridinium, A⁻,(N)—N-methylmorpholinium A⁻, and N—N′-methylpiperazinyl,(N)-bromomethylamido, (N)—N-hexylamino, thiophene, —N⁺(CH₃)₂CO₂H I⁻,—NCH₃CH₂CO₂H, —(N)—N′-dimethylpiperazinium I⁻, (N)-t-butyloxycarbamoyl,(N)-methylsulfonamido, (N)N′-methylpyrrolidinium, and —(OCH₂CH₂)₃I,where A⁻ is a pharmaceutically acceptable anion. The benzo ring can bemono-substituted at the 6, 7 or 8 position, or disubstituted at the 7-and -8 positions. Also included are the 6,7,8-trialkoxy compounds, forexample the 6,7,8-trimethoxy compounds. A variety of other substituentscan be advantageously present on the 6, 7, 8, and/or 9- positions of thebenzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate(e.g., a 5 or 6 carbon monosaccharide), peptide, and quaternary ammoniumsalts linked to the ring via poly(oxyalkylene) linkages, e.g.,—(OCH₂CH₂)_(x)—N⁺R¹³R¹⁴R¹⁵A⁻, where x is 2 to 10. Exemplary compoundsare those set forth below in Table 1. TABLE 1 Alternative compounds #3(Family F101.xxx.yyy)*

Prefix Cpd # (FFF.xxx. yyy) R¹═R² R⁵ (R^(I)q) F101.001 01 n-propyl Ph—7-methyl 02 n-propyl Ph— 7-ethyl 03 n-propyl Ph— 7-iso-propyl 04n-propyl Ph— 7-tert-butyl 05 n-propyl Ph— 7-OH 06 n-propyl Ph— 7-OCH₃ 07n-propyl Ph— 7-O(iso-propyl) 08 n-propyl Ph— 7-SCH₃ 09 n-propyl Ph—7-SOCH₃ 10 n-propyl Ph— 7-SO₂CH₃ 11 n-propyl Ph— 7-SCH₂CH₃ 12 n-propylPh— 7-NH₂ 13 n-propyl Ph— 7-NHOH 14 n-propyl Ph— 7-NHCH₃ 15 n-propyl Ph—7-N(CH₃)₂ 16 n-propyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-propyl Ph— 7-NHC(═O)CH₃ 18n-propyl Ph— 7-N(CH₂CH₃)₂ 19 n-propyl Ph— 7-NMeCH₂CO₂H 20 n-propyl Ph—7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-propyl Ph— 7-(N)-morpholine 22 n-propyl Ph—7-(N)-azetidine 23 n-propyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24n-propyl Ph— 7-(N)-pyrrolidine 25 n-propyl Ph—7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-propyl Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 n-propyl Ph—7-(N)-N′-methylpiperazine 28 n-propyl Ph— 7-(N)-N′-dimethylpiperazinium,I⁻ 29 n-propyl Ph— 7-NH—CBZ 30 n-propyl Ph— 7-NHC(O)C₅H₁₁ 31 n-propylPh— 7-NHC(O)CH₂Br 32 n-propyl Ph— 7-NH—C(NH)NH₂ 33 n-propyl Ph—7-(2)-thiophene 34 n-propyl Ph— 8-methyl 35 n-propyl Ph— 8-ethyl 36n-propyl Ph— 8-iso-propyl 37 n-propyl Ph— 8-tert-butyl 38 n-propyl Ph—8-OH 39 n-propyl Ph— 8-OCH₃ 40 n-propyl Ph— 8-O(iso-propyl) 41 n-propylPh— 8-SCH₃ 42 n-propyl Ph— 8-SOCH₃ 43 n-propyl Ph— 8-SO₂CH₃ 44 n-propylPh— 8-SCH₂CH₃ 45 n-propyl Ph— 8-NH₂ 46 n-propyl Ph— 8-NHOH 47 n-propylPh— 8-NHCH₃ 48 n-propyl Ph— 8-N(CH₃)₂ 49 n-propyl Ph— 8-N⁺(CH₃)₃, I⁻ 50n-propyl Ph— 8-NHC(═O)CH₃ 51 n-propyl Ph— 8-N(CH₂CH₃)₂ 52 n-propyl Ph—8-NMeCH₂CO₂H 53 n-propyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-propyl Ph—8-(N)-morpholine 55 n-propyl Ph— 8-(N)-azetidine 56 n-propyl Ph—8-(N)-N-methylazetidinium, I⁻ 57 n-propyl Ph— 8-(N)-pyrrolidine 58n-propyl Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59 n-propyl Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 n-propyl Ph—8-(N)-N′-methylpiperazine 61 n-propyl Ph— 8-(N)-N′-dimethylpiperazinium,I⁻ 62 n-propyl Ph— 8-NH—CBZ 63 n-propyl Ph— 8-NHC(O)C₅H₁₁ 64 n-propylPh— 8-NHC(O)CH₂Br 65 n-propyl Ph— 8-NH—C(NH)NH₂ 66 n-propyl Ph—8-(2)-thiophene 67 n-propyl Ph— 9-methyl 68 n-propyl Ph— 9-ethyl 69n-propyl Ph— 9-iso-propyl 70 n-propyl Ph— 9-tert-butyl 71 n-propyl Ph—9-OH 72 n-propyl Ph— 9-OCH₃ 73 n-propyl Ph— 9-O(iso-propyl) 74 n-propylPh— 9-SCH₃ 75 n-propyl Ph— 9-SOCH₃ 76 n-propyl Ph— 9-SO₂CH₃ 77 n-propylPh— 9-SCH₂CH₃ 78 n-propyl Ph— 9-NH₂ 79 n-propyl Ph— 9-NHOH 80 n-propylPh— 9-NHCH₃ 81 n-propyl Ph— 9-N(CH₃)₂ 82 n-propyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-propyl Ph— 9-NHC(═O)CH₃ 84 n-propyl Ph— 9-N(CH₂CH₃)₂ 85 n-propyl Ph—9-NMeCH₂CO₂H 86 n-propyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-propyl Ph—9-(N)-morpholine 88 n-propyl Ph— 9-(N)-azetidine 89 n-propyl Ph—9-(N)-N-methylazetidinium, I⁻ 90 n-propyl Ph— 9-(N)-pyrrolidine 91n-propyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-propyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 n-propyl Ph—9-(N)-N′-methylpiperazine 93 n-propyl Ph— 9-(N)-N′-dimethylpiperazinium,I⁻ 95 n-propyl Ph— 9-NH—CBZ 96 n-propyl Ph— 9-NHC(O)C₅H₁₁ 97 n-propylPh— 9-NHC(O)CH₂Br 98 n-propyl Ph— 9-NH—C(NH)NH₂ 99 n-propyl Ph—9-(2)-thiophene 100 n-propyl Ph— 7-OCH₃, 8-OCH₃ 101 n-propyl Ph— 7-SCH₃,8-OCH₃ 102 n-propyl Ph— 7-SCH₃, 8-SCH₃ 103 n-propyl Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.002 01 n-butyl Ph— 7-methyl 02 n-butyl Ph— 7-ethyl 03n-butyl Ph— 7-iso-propyl 04 n-butyl Ph— 7-tert-butyl 05 n-butyl Ph— 7-OH06 n-butyl Ph— 7-OCH₃ 07 n-butyl Ph— 7-O(iso-propyl) 08 n-butyl Ph—7-SCH₃ 09 n-butyl Ph— 7-SOCH₃ 10 n-butyl Ph— 7-SO₂CH₃ 11 n-butyl Ph—7-SCH₂CH₃ 12 n-butyl Ph— 7-NH₂ 13 n-butyl Ph— 7-NHCH 14 n-butyl Ph—7-NHCH₃ 15 n-butyl Ph— 7-N(CH₃)₂ 16 n-butyl Ph— 7-N⁺(CH₃)₃, I⁻ 17n-butyl Ph— 7-NHC(═O)CH₃ 18 n-butyl Ph— 7-N(CH₂CH₃)₂ 19 n-butyl Ph—7-NMeCH₂CO₂H 20 n-butyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-butyl Ph—7-(N)-morpholine 22 n-butyl Ph— 7-(N)-azetidine 23 n-butyl Ph—7-(N)-N-methylazetidinium, I⁻ 24 n-butyl Ph— 7-(N)-pyrrolidine 25n-butyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-butyl Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 n-butyl Ph— 7-(N)-N′-methylpiperazine28 n-butyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 n-butyl Ph— 7-NH—CBZ30 n-butyl Ph— 7-NHC(O)C₅H₁₁ 31 n-butyl Ph— 7-NHC(O)CH₂Br 32 n-butyl Ph—7-NH—C(NH)NH₂ 33 n-butyl Ph— 7-(2)-thiophene 34 n-butyl Ph— 8-methyl 35n-butyl Ph— 8-ethyl 36 n-butyl Ph— 8-iso-propyl 37 n-butyl Ph—8-tert-butyl 38 n-butyl Ph— 8-OH 39 n-butyl Ph— 8-OCH₃ 40 n-butyl Ph—8-O(iso-propyl) 41 n-butyl Ph— 8-SCH₃ 42 n-butyl Ph— 8-SOCH₃ 43 n-butylPh— 8-SO₂CH₃ 44 n-butyl Ph— 8-SCH₂CH₃ 45 n-butyl Ph— 8-NH₂ 46 n-butylPh— 8-NHCH 47 n-butyl Ph— 8-NHCH₃ 48 n-butyl Ph— 8-N(CH₃)₂ 49 n-butylPh— 8-N⁺(CH₃)₃, I⁻ 50 n-butyl Ph— 8-NHC(═O)CH₃ 51 n-butyl Ph—8-N(CH₂CH₃)₂ 52 n-butyl Ph— 8-NMeCH₂CO₂H 53 n-butyl Ph—8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-butyl Ph— 8-(N)-morpholine 55 n-butyl Ph—8-(N)-azetidine 56 n-butyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 n-butylPh— 8-(N)-pyrrolidine 58 n-butyl Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59n-butyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 n-butyl Ph—8-(N)-N′-methylpiperazine 61 n-butyl Ph— 8-(N)-N′-dimethylpiperazinium,I⁻ 62 n-butyl Ph— 8-NH—CBZ 63 n-butyl Ph— 8-NHC(O)C₅H₁₁ 64 n-butyl Ph—8-NHC(O)CH₂Br 65 n-butyl Ph— 8-NH—C(NH)NH₂ 66 n-butyl Ph—8-(2)-thiophene 67 n-butyl Ph— 9-methyl 68 n-butyl Ph— 9-ethyl 69n-butyl Ph— 9-iso-propyl 70 n-butyl Ph— 9-tert-butyl 71 n-butyl Ph— 9-OH72 n-butyl Ph— 9-OCH₃ 73 n-butyl Ph— 9-O(iso-propyl) 74 n-butyl Ph—9-SCH₃ 75 n-butyl Ph— 9-SOCH₃ 76 n-butyl Ph— 9-SO₂CH₃ 77 n-butyl Ph—9-SCH₂CH₃ 78 n-butyl Ph— 9-NH₂ 79 n-butyl Ph— 9-NHOH 80 n-butyl Ph—9-NHCH₃ 81 n-butyl Ph— 9-N(CH₃)₂ 82 n-butyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-butyl Ph— 9-NHC(═O)CH₃ 84 n-butyl Ph— 9-N(CH₂CH₃)₂ 85 n-butyl Ph—9-NMeCH₂CO₂H 86 n-butyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-butyl Ph—9-(N)-morpholine 88 n-butyl Ph— 9-(N)-azetidine 89 n-butyl Ph—9-(N)-N-methylazetidinium, I⁻ 90 n-butyl Ph— 9-(N)-pyrrolidine 91n-butyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-butyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 n-butyl Ph— 9-(N)-N′-methylpiperazine93 n-butyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 n-butyl Ph— 9-NH—CBZ96 n-butyl Ph— 9-NHC(O)C₅H₁₁ 97 n-butyl Ph— 9-NHC(O)CH₂Br 98 n-butyl Ph—9-NH—C(NH)NH₂ 99 n-butyl Ph— 9-(2)-thiophene 100 n-butyl Ph— 7-OCH₃,8-OCH₃ 101 n-butyl Ph— 7-SCH₃, 8-OCH₃ 102 n-butyl Ph— 7-SCH₃, 8-SCH₃ 103n-butyl PH- 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.003 01 n-pentyl Ph— 7-methyl 02n-pentyl Ph— 7-ethyl 03 n-pentyl Ph— 7-iso-propyl 04 n-pentyl Ph—7-tert-butyl 05 n-pentyl Ph— 7-OH 06 n-pentyl Ph— 7-OCH₃ 07 n-pentyl Ph—7-O(iso-propyl) 08 n-pentyl Ph— 7-SCH₃ 09 n-pentyl Ph— 7-SOCH₃ 10n-pentyl Ph— 7-SO₂CH₃ 11 n-pentyl Ph— 7-SCH₂CH₃ 12 n-pentyl Ph— 7-NH₂ 13n-pentyl Ph— 7-NHOH 14 n-pentyl PH- 7-NHCH₃ 15 n-pentyl Ph— 7-N(CH₃)₂ 16n-pentyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-pentyl PH- 7-NHC(═O)CH₃ 18 n-pentyl Ph—7-N(CH₂CH₃)₂ 19 n-pentyl Ph— 7-NMeCH₂CO₂H 20 n-pentyl Ph—7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-pentyl Ph— 7-(N)-morpholine 22 n-pentyl Ph—7-(N)-azetidine 23 n-pentyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24n-pentyl Ph— 7-(N)-pyrrolidine 25 n-pentyl Ph—7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-pentyl Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 n-pentyl Ph—7-(N)-N′-methylpiperazine 28 n-pentyl Ph— 7-(N)-N′-dimethylpiperazinium,I⁻ 29 n-pentyl Ph— 7-NH—CBZ 30 n-pentyl Ph— 7-NHC(O)C₅H₁₁ 31 n-pentylPh— 7-NHC(O)CH₂Br 32 n-pentyl Ph— 7-NH—C(NH)NH₂ 33 n-pentyl Ph—7-(2)-thiophene 34 n-pentyl Ph— 8-methyl 35 n-pentyl Ph— 8-ethyl 36n-pentyl Ph— 8-iso-propyl 37 n-pentyl Ph— 8-tert-butyl 38 n-pentyl Ph—8-OH 39 n-pentyl Ph— 8-OCH₃ 40 n-pentyl Ph— 8-O(iso-propyl) 41 n-pentylPh— 8-SCH₃ 42 n-pentyl Ph— 8-SOCH₃ 43 n-pentyl Ph— 8-SO₂CH₃ 44 n-pentylPh— 8-SCH₂CH₃ 45 n-pentyl Ph— 8-NH₂ 46 n-pentyl Ph— 8-NHOH 47 n-pentylPh— 8-NHCH₃ 48 n-pentyl Ph— 8-N(CH₃)₂ 49 n-pentyl Ph— 8-N⁺(CH₃)₃, I⁻ 50n-pentyl Ph— 8-NHC(═O)CH₃ 51 n-pentyl Ph— 8-N(CH₂CH₃)₂ 52 n-pentyl Ph—8-NMeCH₂CO₂H 53 n-pentyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-pentyl Ph—8-(N)-morpholine 55 n-pentyl Ph— 8-(N)-azetidine 56 n-pentyl Ph—8-(N)-N-methylazetidinium, I⁻ 57 n-pentyl Ph— 8-(N)-pyrrolidine 58n-pentyl Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59 n-pentyl Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 n-pentyl Ph—8-(N)-N′-methylpiperazine 61 n-pentyl Ph— 8-(N)-N′-dimethylpiperazinium,I⁻ 62 n-pentyl Ph— 8-NH—CBZ 63 n-pentyl Ph— 8-NHC(O)C₅H₁₁ 64 n-pentylPh— 8-NHC(O)CH₂Br 65 n-pentyl Ph— 8-NH—C(NH)NH₂ 66 n-pentyl Ph—8-(2)-thiophene 67 n-pentyl Ph— 9-methyl 68 n-pentyl Ph— 9-ethyl 69n-pentyl Ph— 9-iso-propyl 70 n-pentyl Ph— 9-tert-butyl 71 n-pentyl Ph—9-OH 72 n-pentyl Ph— 9-OCH₃ 73 n-pentyl Ph— 9-O(iso-propyl) 74 n-pentylPh— 9-SCH₃ 75 n-pentyl Ph— 9-SOCH₃ 76 n-pentyl Ph— 9-SO₂CH₃ 77 n-pentylPh— 9-SCH₂CH₃ 78 n-pentyl Ph— 9-NH₂ 79 n-pentyl Ph— 9-NHOH 80 n-pentylPh— 9-NHCH₃ 81 n-pentyl Ph— 9-N(CH₃)₂ 82 n-pentyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-pentyl Ph— 9-NHC(═O)CH₃ 84 n-pentyl Ph— 9-N(CH₂CH₃)₂ 85 n-pentyl Ph—9-NMeCH₂CO₂H 86 n-pentyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-pentyl Ph—9-(N)-morpholine 88 n-pentyl Ph— 9-(N)-azetidine 89 n-pentyl Ph—9-(N)-N-methylazetidinium, I⁻ 90 n-pentyl Ph— 9-(N)-pyrrolidine 91n-pentyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-pentyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 n-pentyl Ph—9-(N)-N′-methylpiperazine 93 n-pentyl Ph— 9-(N)-N′-dimethylpiperazinium,I⁻ 95 n-pentyl Ph— 9-NH—CBZ 96 n-pentyl Ph— 9-NHC(O)C₅H₁₁ 97 n-pentylPh— 9-NHC(O)CH₂Br 98 n-pentyl Ph— 9-NH—C(NH)NH₂ 99 n-pentyl Ph—9-(2)-thiophene 100 n-pentyl Ph— 7-OCH₃, 8-OCH₃ 101 n-pentyl Ph— 7-SCH₃,8-OCH₃ 102 n-pentyl Ph— 7-SCH₃, 8-SCH₃ 103 n-pentyl Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.004 01 n-hexyl Ph— 7-methyl 02 n-hexyl Ph— 7-ethyl 03n-hexyl Ph— 7-iso-propyl 04 n-hexyl Ph— 7-tert-butyl 05 n-hexyl Ph— 7-OH06 n-hexyl Ph— 7-OCH₃ 07 n-hexyl Ph— 7-O-(iso-propyl) 08 n-hexyl Ph—7-SCH₃ 09 n-hexyl Ph— 7-SOCH₃ 10 n-hexyl Ph— 7-SO₂CH₃ 11 n-hexyl Ph—7-SCH₂CH₃ 12 n-hexyl Ph— 7-NH₂ 13 n-hexyl Ph— 7-NHOH 14 n-hexyl Ph—7-NHCH₃ 15 n-hexyl Ph— 7-N(CH₃)₂ 16 n-hexyl Ph— 7-N⁺(CH₃)₃, I⁻ 17n-hexyl Ph— 7-NHC(═O)CH₃ 18 n-hexyl Ph— 7-N(CH₂CH₃)₂ 19 n-hexyl Ph—7-NMeCH₂CO₂H 20 n-hexyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-hexyl Ph—7-(N)-morpholine 22 n-hexyl Ph— 7-(N)-azetidine 23 n-hexyl Ph—7-(N)-N-methylazetidinium, I⁻ 24 n-hexyl Ph— 7-(N)-pyrrolidine 25n-hexyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 n-hexyl Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 n-hexyl Ph— 7-(N)-N′-methylpiperazine28 n-hexyl Ph— 7-(N)-N′-dimethylpiperazinium, I⁻ 29 n-hexyl Ph— 7-NH—CBZ30 n-hexyl Ph— 7-NHC(O)C₅H₁₁ 31 n-hexyl Ph— 7-NHC(O)CH₂Br 32 n-hexyl Ph—7-NH—C(NH)NH₂ 33 n-hexyl Ph— 7-(2)-thiophene 34 n-hexyl Ph— 8-methyl 35n-hexyl Ph— 8-ethyl 36 n-hexyl Ph— 8-iso-propyl 37 n-hexyl Ph—8-tert-butyl 38 n-hexyl Ph— 8-OH 39 n-hexyl Ph— 8-OCH₃ 40 n-hexyl Ph—8-O(iso-propyl) 41 n-hexyl Ph— 8-SCH₃ 42 n-hexyl Ph— 8-SOCH₃ 43 n-hexylPh— 8-SO₂CH₃ 44 n-hexyl Ph— 8-SCH₂CH₃ 45 n-hexyl Ph— 8-NH₂ 46 n-hexylPh— 8-NHOH 47 n-hexyl Ph— 8-NHCH₃ 48 n-hexyl Ph— 8-N(CH₃)₂ 49 n-hexylPh— 8-NH(CH₃)₃, I⁻ 50 n-hexyl Ph— 8-NHC(═O)CH₃ 51 n-hexyl Ph—8-N(CH₂CH₃)₂ 52 n-hexyl Ph— 8-NMeCH₂CO₂H 53 n-hexyl Ph—8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-hexyl Ph— 8-(N)-morpholine 55 n-hexyl Ph—8-(N)-azetidine 56 n-hexyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57 n-hexylPh— 8-(N)-pyrrolidine 58 n-hexyl Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59n-hexyl Ph— 8-(N)-N-methyl-morpholinium, I⁻ 60 n-hexyl Ph—8-(N)-N′-methylpiperazine 61 n-hexyl Ph— 8-(N)-N′-dimethylpiperazinium,I⁻ 62 n-hexyl Ph— 8-NH—CBZ 63 n-hexyl Ph— 8-NHC(O)C₅H₁₁ 64 n-hexyl Ph—8-NHC(O)CH₂Br 65 n-hexyl Ph— 8-NH—C(NH)NH₂ 66 n-hexyl Ph—8-(2)-thiophene 67 n-hexyl Ph— 9-methyl 68 n-hexyl Ph— 9-ethyl 69n-hexyl Ph— 9-iso-propyl 70 n-hexyl Ph— 9-tert-butyl 71 n-hexyl Ph— 9-OH72 n-hexyl Ph— 9-OCH₃ 73 n-hexyl Ph— 9-O(iso-propyl) 74 n-hexyl Ph—9-SCH₃ 75 n-hexyl Ph— 9-SOCH₃ 76 n-hexyl Ph— 9-SO₂CH₃ 77 n-hexyl Ph—9-SCH₂CH₃ 78 n-hexyl Ph— 9-NH₂ 79 n-hexyl Ph— 9-NHOH 80 n-hexyl Ph—9-NHCH₃ 81 n-hexyl Ph— 9-N(CH₃)₂ 82 n-hexyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-hexyl Ph— 9-NHC(═O)CH₃ 84 n-hexyl Ph— 9-N(CH₂CH₃)₂ 85 n-hexyl Ph—9-NMeCH₂CO₂H 86 n-hexyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-hexyl Ph—9-(N)-morpholine 88 n-hexyl Ph— 9-(N)-azetidine 89 n-hexyl Ph—9-(N)-N-methylazetidinium, I⁻ 90 n-hexyl Ph— 9-(N)-pyrrolidine 91n-hexyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 n-hexyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 n-hexyl Ph— 9-(N)-N′-methylpiperazine93 n-hexyl Ph— 9-(N)-N′-dimethylpiperazinium, I⁻ 95 n-hexyl Ph— 9-NH—CBZ96 n-hexyl Ph— 9-NHC(O)C₅H₁₁ 97 n-hexyl Ph— 9-NHC(O)CH₂Br 98 n-hexyl Ph—9-NH—C(NH)NH₂ 99 n-hexyl Ph— 9-(2)-thiophene 100 n-hexyl Ph— 7-OCH₃,8-OCH₃ 101 n-hexyl Ph— 7-SCH₃, 8-OCH₃ 102 n-hexyl Ph— 7-SCH₃, 8-SCH₃ 103n-hexyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.005 01 iso-propyl Ph— 7-methyl02 iso-propyl Ph— 7-ethyl 03 iso-propyl Ph— 7-iso-propyl 04 iso-propylPh— 7-tert-butyl 05 iso-propyl Ph— 7-OH 06 iso-propyl Ph— 7-OCH₃ 07iso-propyl Ph— 7-O(iso-propyl) 08 iso-propyl Ph— 7-SCH₃ 09 iso-propylPh— 7-SOCH₃ 10 iso-propyl Ph— 7-SO₂CH₃ 11 iso-propyl Ph— 7-SCH₂CH₃ 12iso-propyl Ph— 7-NH₂ 13 iso-propyl Ph— 7-NHOH 14 iso-propyl Ph— 7-NHCH₃15 iso-propyl Ph— 7-N(CH₃)₂ 16 iso-propyl Ph— 7-N⁺(CH₃)₃, I⁻ 17iso-propyl Ph— 7-NHC(═O)CH₃ 18 iso-propyl Ph— 7-N(CH₂CH₃)₂ 19 iso-propylPh— 7-NMeCH₂CO₂H 20 iso-propyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-propylPh— 7-(N)-morpholine 22 iso-propyl Ph— 7-(N)-azetidine 23 iso-propyl Ph—7-(N)-N-methylazetidinium, I⁻ 24 iso-propyl Ph— 7-(N)-pyrrolidine 25iso-propyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 iso-propyl Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 iso-propyl Ph—7-(N)-N′-methylpiperazine 28 iso-propyl Ph—7-(N)-N′-dimethylpiperazinium, I⁻ 29 iso-propyl Ph— 7-NH—CBZ 30iso-propyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-propyl Ph— 7-NHC(O)CH₂Br 32iso-propyl Ph— 7-NH—C(NH)NH₂ 33 iso-propyl Ph— 7-(2)-thiophene 34iso-propyl Ph— 8-methyl 35 iso-propyl Ph— 8-ethyl 36 iso-propyl Ph—8-iso-propyl 37 iso-propyl Ph— 8-tert-butyl 38 iso-propyl Ph— 8-OH 39iso-propyl Ph— 8-OCH₃ 40 iso-propyl PH- 8-O(iso-propyl) 41 iso-propylPh— 8-SCH₃ 42 iso-propyl Ph— 8-SOCH₃ 43 iso-propyl Ph— 8-SO₂CH₃ 44iso-propyl Ph— 8-SCH₂CH₃ 45 iso-propyl Ph— 8-NH₂ 46 iso-propyl Ph—8-NHOH 47 iso-propyl Ph— 8-NHCH₃ 48 iso-propyl Ph— 8-N(CH₃)₂ 49iso-propyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-propyl Ph— 8-NHC(═O)CH₃ 51iso-propyl Ph— 8-N(CH₂CH₃)₂ 52 iso-propyl Ph— 8-NMeCH₂CO₂H 53 iso-propylPh— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-propyl Ph— 8-(N)-morpholine 55iso-propyl Ph— 8-(N)-azetidine 56 iso-propyl Ph—8-(N)-N-methylazetidinium, I⁻ 57 iso-propyl Ph— 8-(N)-pyrrolidine 58iso-propyl Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59 iso-propyl Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 iso-propyl Ph—8-(N)-N′-methylpiperazine 61 iso-propyl Ph—8-(N)-N′-dimethylpiperazinium, I⁻ 62 iso-propyl Ph— 8-NH—CBZ 63iso-propyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-propyl Ph— 8-NHC(O)CH₂Br 65iso-propyl Ph— 8-NH—C(NH)NH₂ 66 iso-propyl Ph— 8-(2)-thiophene 67iso-propyl Ph— 9-methyl 68 iso-propyl Ph— 9-ethyl 69 iso-propyl Ph—9-iso-propyl 70 iso-propyl Ph— 9-tert-butyl 71 iso-propyl Ph— 9-OH 72iso-propyl Ph— 9-OCH₃ 73 iso-propyl Ph— 9-O(iso-propyl) 74 iso-propylPh— 9-SCH₃ 75 iso-propyl Ph— 9-SOCH₃ 76 iso-propyl Ph— 9-SO₂CH₃ 77iso-propyl Ph— 9-SCH₂CH₃ 78 iso-propyl Ph— 9-NH₂ 79 iso-propyl Ph—9-NHOH 80 iso-propyl Ph— 9-NHCH₃ 81 iso-propyl Ph— 9-N(CH₃)₂ 82iso-propyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-propyl Ph— 9-NHC(═O)CH₃ 84iso-propyl Ph— 9-N(CH₂CH₃)₂ 85 iso-propyl Ph— 9-NMeCH₂CO₂H 86 iso-propylPh— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-propyl Ph— 9-(N)-morpholine 88iso-propyl Ph— 9-(N)-azetidine 89 iso-propyl Ph—9-(N)-N-methylazetidinium, I⁻ 90 iso-propyl Ph— 9-(N)-pyrrolidine 91iso-propyl PH- 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 iso-propyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 iso-propyl Ph—9-(N)-N′-methylpiperazine 93 iso-propyl Ph—9-(N)-N′-dimethylpiperazinium, I⁻ 95 iso-propyl Ph— 9-NH—CBZ 96iso-propyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-propyl Ph— 9-NHC(O)CH₂Br 98iso-propyl Ph— 9-NH—C(NH)NH₂ 99 iso-propyl Ph— 9-(2)-thiophene 100iso-propyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-propyl Ph— 7-SCH₃, 8-OCH₃ 102iso-propyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-propyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃F101.006 01 iso-butyl Ph— 7-methyl 02 iso-butyl Ph— 7-ethyl 03 iso-butylPh— 7-iso-propyl 04 iso-butyl Ph— 7-tert-butyl 05 iso-butyl Ph— 7-OH 06iso-butyl Ph— 7-OCH₃ 07 iso-butyl Ph— 7-O(iso-propyl) 08 iso-butyl Ph—7-SCH₃ 09 iso-butyl Ph— 7-SOCH₃ 10 iso-butyl Ph— 7-SO₂CH₃ 11 iso-butylPh— 7-SCH₂CH₃ 12 iso-butyl Ph— 7-NH₂ 13 iso-butyl Ph— 7-NHOH 14iso-butyl Ph— 7-NHCH₃ 15 iso-butyl Ph— 7-N(CH₃)₂ 16 iso-butyl Ph—7-N⁺(CH₃)₃, I⁻ 17 iso-butyl Ph— 7-NHC(═O)CH₃ 18 iso-butyl Ph—7-N(CH₂CH₃)₂ 19 iso-butyl Ph— 7-NMeCH₂CO₂H 20 iso-butyl Ph—7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-butyl Ph— 7-(N)-morpholine 22 iso-butyl Ph—7-(N)-azetidine 23 iso-butyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24iso-butyl Ph— 7-(N)-pyrrolidine 25 iso-butyl Ph—7-(N)-N-methyl-pyrrolidinium, I⁻ 26 iso-butyl Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 iso-butyl Ph—7-(N)-N′-methylpiperazine 28 iso-butyl Ph—7-(N)-N′-dimethylpiperazinium, I⁻ 29 iso-butyl Ph— 7-NH—CBZ 30 iso-butylPh— 7-NHC(O)C₅H₁₁ 31 iso-butyl Ph— 7-NHC(O)CH₂Br 32 iso-butyl Ph—7-NH—C(NH)NH₂ 33 iso-butyl Ph— 7-(2)-thiophene 34 iso-butyl Ph— 8-methyl35 iso-butyl Ph— 8-ethyl 36 iso-butyl Ph— 8-iso-propyl 37 iso-butyl Ph—8-tert-butyl 38 iso-butyl Ph— 8-OH 39 iso-butyl Ph— 8-OCH₃ 40 iso-butylPh— 8-O(iso-propyl) 41 iso-butyl Ph— 8-SCH₃ 42 iso-butyl Ph— 8-SOCH₃ 43iso-butyl Ph— 8-SO₂CH₃ 44 iso-butyl Ph— 8-SCH₂CH₃ 45 iso-butyl Ph— 8-NH₂46 iso-butyl Ph— 8-NHOH 47 iso-butyl Ph— 8-NHCH₃ 48 iso-butyl Ph—8-N(CH₃)₂ 49 iso-butyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-butyl Ph— 8-NHC(═O)CH₃51 iso-butyl Ph— 8-N(CH₂CH₃)₂ 52 iso-butyl Ph— 8-NMeCH₂CO₂H 53 iso-butylPh— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-butyl Ph— 8-(N)-morpholine 55 iso-butylPh— 8-(N)-azetidine 56 iso-butyl Ph— 8-(N)-N-methylazetidinium, I⁻ 57iso-butyl Ph— 8-(N)-pyrrolidine 58 iso-butyl Ph—8-(N)-N-methyl-pyrrolidinium, I⁻ 59 iso-butyl Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 iso-butyl Ph—8-(N)-N′-methylpiperazine 61 iso-butyl Ph—8-(N)-N′-dimethylpiperazinium, I⁻ 62 iso-butyl Ph— 8-NH—CBZ 63 iso-butylPh— 8-NHC(O)C₅H₁₁ 64 iso-butyl Ph— 8-NHC(O)CH₂Br 65 iso-butyl Ph—8-NH—C(NH)NH₂ 66 iso-butyl Ph— 8-(2)-thiophene 67 iso-butyl Ph— 9-methyl68 iso-butyl Ph— 9-ethyl 69 iso-butyl Ph— 9-iso-propyl 70 iso-butyl Ph—9-tert-butyl 71 iso-butyl Ph— 9-OH 72 iso-butyl Ph— 9-OCH₃ 73 iso-butylPh— 9-O(iso-propyl) 74 iso-butyl Ph— 9-SCH₃ 75 iso-butyl Ph— 9-SOCH₃ 76iso-butyl Ph— 9-SO₂CH₃ 77 iso-butyl Ph— 9-SCH₂CH₃ 78 iso-butyl Ph— 9-NH₂79 iso-butyl Ph— 9-NHOH 80 iso-butyl Ph— 9-NHCH₃ 81 iso-butyl Ph—9-N(CH₃)₂ 82 iso-butyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-butyl Ph— 9-NHC(═O)CH₃84 iso-butyl Ph— 9-N(CH₂CH₃)₂ 85 iso-butyl Ph— 9-NMeCH₂CO₂H 86 iso-butylPh— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-butyl Ph— 9-(N)-morpholine 88 iso-butylPh— 9-(N)-azetidine 89 iso-butyl Ph— 9-(N)-N-methylazetidinium, I⁻ 90iso-butyl Ph— 9-(N)-pyrrolidine 91 iso-butyl Ph—9-(N)-N-methyl-pyrrolidinium, I⁻ 92 iso-butyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 iso-butyl Ph—9-(N)-N′-methylpiperazine 93 iso-butyl Ph—9-(N)-N′-dimethylpiperazinium, I⁻ 95 iso-butyl Ph— 9-NH—CBZ 96 iso-butylPh— 9-NHC(O)C₅H₁₁ 97 iso-butyl Ph— 9-NHC(O)CH₂Br 98 iso-butyl Ph—9-NH—C(NH)NH₂ 99 iso-butyl Ph— 9-(2)-thiophene 100 iso-butyl Ph— 7-OCH₃,8-OCH₃ 101 iso-butyl Ph— 7-SCH₃, 8-OCH₃ 102 iso-butyl Ph— 7-SCH₃, 8-SCH₃103 iso-butyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.007 01 iso-pentyl Ph—7-methyl 02 iso-pentyl Ph— 7-ethyl 03 iso-pentyl Ph— 7-iso-propyl 04iso-pentyl Ph— 7-tert-butyl 05 iso-pentyl Ph— 7-OH 06 iso-pentyl Ph—7-OCH₃ 07 iso-pentyl Ph— 7-O(iso-propyl) 08 iso-pentyl Ph— 7-SCH₃ 09iso-pentyl Ph— 7-SOCH₃ 10 iso-pentyl Ph— 7-SO₂CH₃ 11 iso-pentyl Ph—7-SCH₂CH₃ 12 iso-pentyl Ph— 7-NH₂ 13 iso-pentyl Ph— 7-NHOH 14 iso-pentylPh— 7-NHCH₃ 15 iso-pentyl Ph— 7-N(CH₃)₂ 16 iso-pentyl Ph— 7-N⁺(CH₃)₃, I⁻17 iso-pentyl Ph— 7-NHC(═O)CH₃ 18 iso-pentyl Ph— 7-N(CH₂CH₃)₂ 19iso-pentyl Ph— 7-NMeCH₂CO₂H 20 iso-pentyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21iso-pentyl Ph— 7-(N)-morpholine 22 iso-pentyl Ph— 7-(N)-azetidine 23iso-pentyl Ph— 7-(N)-N-methylazetidinium, I⁻ 24 iso-pentyl Ph—7-(N)-pyrrolidine 25 iso-pentyl Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26iso-pentyl Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 iso-pentyl Ph—7-(N)-N′-methylpiperazine 28 iso-pentyl Ph—7-(N)-N′-dimethylpiperazinium, I⁻ 29 iso-pentyl Ph— 7-NH—CBZ 30iso-pentyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-pentyl Ph— 7-NHC(O)CH₂Br 32iso-pentyl Ph— 7-NH—C(NH)NH₂ 33 iso-pentyl Ph— 7-(2)-thiophene 34iso-pentyl Ph— 8-methyl 35 iso-pentyl Ph— 8-ethyl 36 iso-pentyl Ph—8-iso-propyl 37 iso-pentyl Ph— 8-tert-butyl 38 iso-pentyl Ph— 8-OH 39iso-pentyl Ph— 8-OCH₃ 40 iso-pentyl Ph— 8-O(iso-propyl) 41 iso-pentylPh— 8-SCH₃ 42 iso-pentyl Ph— 8-SOCH₃ 43 iso-pentyl Ph— 8-SO₂CH₃ 44iso-pentyl Ph— 8-SCH₂CH₃ 45 iso-pentyl Ph— 8-NH₂ 46 iso-pentyl Ph—8-NHOH 47 iso-pentyl Ph— 8-NHCH₃ 48 iso-pentyl Ph— 8-N(CH₃)₂ 49iso-pentyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-pentyl Ph— 8-NHC(═O)CH₃ 51iso-pentyl Ph— 8-N(CH₂CH₃)₂ 52 iso-pentyl Ph— 8-NMeCH₂CO₂H 53 iso-pentylPh— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-pentyl Ph— 8-(N)-morpholine 55iso-pentyl Ph— 8-(N)-azetidine 56 iso-pentyl Ph—8-(N)-N-methylazetidinium, I⁻ 57 iso-pentyl Ph— 8-(N)-pyrrolidine 58iso-pentyl Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59 iso-pentyl Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 iso-pentyl Ph—8-(N)-N′-methylpiperazine 61 iso-pentyl Ph—8-(N)-N′-dimethylpiperazinium, I⁻ 62 iso-pentyl Ph— 8-NH—CBZ 63iso-pentyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-pentyl Ph— 8-NHC(O)CH₂Br 65iso-pentyl Ph— 8-NH—C(NH)NH₂ 66 iso-pentyl Ph— 8-(2)-thiophene 67iso-pentyl Ph— 9-methyl 68 iso-pentyl Ph— 9-ethyl 69 iso-pentyl Ph—9-iso-propyl 70 iso-pentyl Ph— 9-tert-butyl 71 iso-pentyl Ph— 9-OH 72iso-pentyl Ph— 9-OCH₃ 73 iso-pentyl Ph— 9-O(iso-propyl) 74 iso-pentylPh— 9-SCH₃ 75 iso-pentyl Ph— 9-SOCH₃ 76 iso-pentyl Ph— 9-SO₂CH₃ 77iso-pentyl Ph— 9-SCH₂CH₃ 78 iso-pentyl Ph— 9-NH₂ 79 iso-pentyl Ph—9-NHOH 80 iso-pentyl Ph— 9-NHCH₃ 81 iso-pentyl Ph— 9-N(CH₃)₂ 82iso-pentyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-pentyl Ph— 9-NHC(═O)CH₃ 84iso-pentyl Ph— 9-N(CH₂CH₃)₂ 85 iso-pentyl Ph— 9-NMeCH₂CO₂H 86 iso-pentylPh— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-pentyl Ph— 9-(N)-morpholine 88iso-pentyl Ph— 9-(N)-azetidine 89 iso-pentyl Ph—9-(N)-N-methylazetidinium, I⁻ 90 iso-pentyl Ph— 9-(N)-pyrrolidine 91iso-pentyl Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 iso-pentyl Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 iso-pentyl Ph—9-(N)-N′-methylpiperazine 93 iso-pentyl Ph—9-(N)-N′-dimethylpiperazinium, I⁻ 95 iso-pentyl Ph— 9-NH—CBZ 96iso-pentyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-pentyl Ph— 9-NHC(O)CH₂Br 98iso-pentyl Ph— 9-NH—C(NH)NH₂ 99 iso-pentyl Ph— 9-(2)-thiophene 100iso-pentyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-pentyl Ph— 7-SCH₃, 8-OCH₃ 102iso-pentyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-pentyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃F101.008 01 CH₂C(═O)C₂H₅ Ph— 7-methyl 02 CH₂C(═O)C₂H₅ Ph— 7-ethyl 03CH₂C(═O)C₂H₅ Ph— 7-iso-propyl 04 CH₂C(═O)C₂H₅ Ph— 7-tert-butyl 05CH₂C(═O)C₂H₅ Ph— 7-OH 06 CH₂C(═O)C₂H₅ Ph— 7-OCH₃ 07 CH₂C(═O)C₂H₅ Ph—7-O(iso-propyl) 08 CH₂C(═O)C₂H₅ Ph— 7-SCH₃ 09 CH₂C(═O)C₂H₅ Ph— 7-SOCH₃10 CH₂C(═O)C₂H₅ Ph— 7-SO₂CH₃ 11 CH₂C(═O)C₂H₅ Ph— 7-SCH₂CH₃ 12CH₂C(═O)C₂H₅ Ph— 7-NH₂ 13 CH₂C(═O)C₂H₅ Ph— 7-NHOH 14 CH₂C(═O)C₂H₅ Ph—7-NHCH₃ 15 CH₂C(═O)C₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂C(═O)C₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻17 CH₂C(═O)C₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂C(═O)C₂H₅ Ph— 7-N(CH₂CH₃)₂ 19CH₂C(═O)C₂H₅ Ph— 7-NMeCH₂CO₂H 20 CH₂C(═O)C₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻21 CH₂C(═O)C₂H₅ Ph— 7-(N)-morpholine 22 CH₂C(═O)C₂H₅ Ph— 7-(N)-azetidine23 CH₂C(═O)C₂H₅ Ph— 7-(N)-N-methylazetidinium, I⁻ 24 CH₂C(═O)C₂H₅ Ph—7-(N)-pyrrolidine 25 CH₂C(═O)C₂H₅ Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻26 CH₂C(═O)C₂H₅ Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂C(═O)C₂H₅ Ph—7-(N)-N′-methylpiperazine 28 CH₂C(═O)C₂H₅ Ph—7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂C(═O)C₂H₅ Ph— 7-NH—CBZ 30CH₂C(═O)C₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂C(═O)C₂H₅ Ph— 7-NHC(O)CH₂Br 32CH₂C(═O)C₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂C(═O)C₂H₅ Ph— 7-(2)-thiophene 34CH₂C(═O)C₂H₅ Ph— 8-methyl 35 CH₂C(═O)C₂H₅ Ph— 8-ethyl 36 CH₂C(═O)C₂H₅Ph— 8-iso-propyl 37 CH₂C(═O)C₂H₅ Ph— 8-tert-butyl 38 CH₂C(═O)C₂H₅ Ph—8-OH 39 CH₂C(═O)C₂H₅ Ph— 8-OCH₃ 40 CH₂C(═O)C₂H₅ Ph— 8-O(iso-propyl) 41CH₂C(═O)C₂H₅ Ph— 8-SCH₃ 42 CH₂C(═O)C₂H₅ Ph— 8-SOCH₃ 43 CH₂C(═O)C₂H₅ Ph—8-SO₂CH₃ 44 CH₂C(═O)C₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂C(═O)C₂H₅ Ph— 8-NH₂ 46CH₂C(═O)C₂H₅ Ph— 8-NHOH 47 CH₂C(═O)C₂H₅ Ph— 8-NHCH₃ 48 CH₂C(═O)C₂H₅ Ph—8-N(CH₃)₂ 49 CH₂C(═O)C₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂C(═O)C₂H₅ Ph—8-NHC(═O)CH₃ 51 CH₂C(═O)C₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂C(═O)C₂H₅ Ph—8-NMeCH₂CO₂H 53 CH₂C(═O)C₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂C(═O)C₂H₅Ph— 8-(N)-morpholine 55 CH₂C(═O)C₂H₅ Ph— 8-(N)-azetidine 56 CH₂C(═O)C₂H₅Ph— 8-(N)-N-methylazetidinium, I⁻ 57 CH₂C(═O)C₂H₅ Ph— 8-(N)-pyrrolidine58 CH₂C(═O)C₂H₅ Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59 CH₂C(═O)C₂H₅ Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂C(═O)C₂H₅ Ph—8-(N)-N′-methylpiperazine 61 CH₂C(═O)C₂H₅ Ph—8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂C(═O)C₂H₅ Ph— 8-NH—CBZ 63CH₂C(═O)C₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂C(═O)C₂H₅ Ph— 8-NHC(O)CH₂Br 65CH₂C(═O)C₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂C(═O)C₂H₅ Ph— 8-(2)-thiophene 67CH₂C(═O)C₂H₅ Ph— 9-methyl 68 CH₂C(═O)C₂H₅ Ph— 9-ethyl 69 CH₂C(═O)C₂H₅Ph— 9-iso-propyl 70 CH₂C(═O)C₂H₅ Ph— 9-tert-butyl 71 CH₂C(═O)C₂H₅ Ph—9-OH 72 CH₂C(═O)C₂H₅ Ph— 9-OCH₃ 73 CH₂C(═O)C₂H₅ Ph— 9-O(iso-propyl) 74CH₂C(═O)C₂H₅ Ph— 9-SCH₃ 75 CH₂C(═O)C₂H₅ Ph— 9-SOCH₃ 76 CH₂C(═O)C₂H₅ Ph—9-SO₂CH₃ 77 CH₂C(═O)C₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂C(═O)C₂H₅ Ph— 9-NH₂ 79CH₂C(═O)C₂H₅ Ph— 9-NHOH 80 CH₂C(═O)C₂H₅ Ph— 9-NHCH₃ 81 CH₂C(═O)C₂H₅ Ph—9-N(CH₃)₂ 82 CH₂C(═O)C₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂C(═O)C₂H₅ Ph—9-NHC(═O)CH₃ 84 CH₂C(═O)C₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂C(═O)C₂H₅ Ph—9-NMeCH₂CO₂H 86 CH₂C(═O)C₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂C(═O)C₂H₅Ph— 9-(N)-morpholine 88 CH₂C(═O)C₂H₅ Ph— 9-(N)-azetidine 89 CH₂C(═O)C₂H₅Ph— 9-(N)-N-methylazetidinium, I⁻ 90 CH₂C(═O)C₂H₅ Ph— 9-(N)-pyrrolidine91 CH₂C(═O)C₂H₅ Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂C(═O)C₂H₅ Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂C(═O)C₂H₅ Ph—9-(N)-N′-methylpiperazine 93 CH₂C(═O)C₂H₅ Ph—9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂C(═O)C₂H₅ Ph— 9-NH—CBZ 96CH₂C(═O)C₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂C(═O)C₂H₅ Ph— 9-NHC(O)CH₂Br 98CH₂C(═O)C₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂C(═O)C₂H₅ Ph— 9-(2)-thiophene 100CH₂C(═O)C₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂C(═O)C₂H₅ Ph— 7-SCH₃, 8-OCH₃ 102CH₂C(═O)C₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂C(═O)C₂H₅ Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.009 01 CH₂OC₂H₅ Ph— 7-methyl 02 CH₂OC₂H₅ Ph— 7-ethyl 03CH₂OC₂H₅ Ph— 7-iso-propyl 04 CH₂OC₂H₅ Ph— 7-tert-butyl 05 CH₂OC₂H₅ Ph—7-OH 06 CH₂OC₂H₅ Ph— 7-OCH₃ 07 CH₂OC₂H₅ Ph— 7-O(iso-propyl) 08 CH₂OC₂H₅Ph— 7-SCH₃ 09 CH₂OC₂H₅ Ph— 7-SOCH₃ 10 CH₂OC₂H₅ Ph— 7-SO₂CH₃ 11 CH₂OC₂H₅Ph— 7-SCH₂CH₃ 12 CH₂OC₂H₅ Ph— 7-NH₂ 13 CH₂OC₂H₅ Ph— 7-NHOH 14 CH₂OC₂H₅Ph— 7-NHCH₃ 15 CH₂OC₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂OC₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17CH₂OC₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂OC₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂OC₂H₅ Ph—7-NMeCH₂CO₂H 20 CH₂OC₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂OC₂H₅ Ph—7-(N)-morpholine 22 CH₂OC₂H₅ Ph— 7-(N)-azetidine 23 CH₂OC₂H₅ Ph—7-(N)-N-methylazetidinium, I⁻ 24 CH₂OC₂H₅ Ph— 7-(N)-pyrrolidine 25CH₂OC₂H₅ Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂OC₂H₅ Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂OC₂H₅ Ph—7-(N)-N′-methylpiperazine 28 CH₂OC₂H₅ Ph— 7-(N)-N′-dimethylpiperazinium,I⁻ 29 CH₂OC₂H₅ Ph— 7-NH—CBZ 30 CH₂OC₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂OC₂H₅Ph— 7-NHC(O)CH₂Br 32 CH₂OC₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂OC₂H₅ Ph—7-(2)-thiophene 34 CH₂OC₂H₅ Ph— 8-methyl 35 CH₂OC₂H₅ Ph— 8-ethyl 36CH₂OC₂H₅ Ph— 8-iso-propyl 37 CH₂OC₂H₅ Ph— 8-tert-butyl 38 CH₂OC₂H₅ Ph—8-OH 39 CH₂OC₂H₅ Ph— 8-OCH₃ 40 CH₂OC₂H₅ Ph— 8-O(iso-propyl) 41 CH₂OC₂H₅Ph— 8-SCH₃ 42 CH₂OC₂H₅ Ph— 8-SOCH₃ 43 CH₂OC₂H₅ Ph— 8-SO₂CH₃ 44 CH₂OC₂H₅Ph— 8-SCH₂CH₃ 45 CH₂OC₂H₅ Ph— 8-NH₂ 46 CH₂OC₂H₅ Ph— 8-NHOH 47 CH₂OC₂H₅Ph— 8-NHCH₃ 48 CH₂OC₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂OC₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50CH₂OC₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂OC₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂OC₂H₅ Ph—8-NMeCH₂CO₂H 53 CH₂OC₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂OC₂H₅ Ph—8-(N)-morpholine 55 CH₂OC₂H₅ Ph— 8-(N)-azetidine 56 CH₂OC₂H₅ Ph—8-(N)-N-methylazetidinium, I⁻ 57 CH₂OC₂H₅ Ph— 8-(N)-pyrrolidine 58CH₂OC₂H₅ Ph— 8-(N)-N-methyl-pyrrolidinium, I⁻ 59 CH₂OC₂H₅ Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂OC₂H₅ Ph—8-(N)-N′-methylpiperazine 61 CH₂OC₂H₅ Ph— 8-(N)-N′-dimethylpiperazinium,I⁻ 62 CH₂OC₂H₅ Ph— 8-NH—CBZ 63 CH₂OC₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂OC₂H₅Ph— 8-NHC(O)CH₂Br 65 CH₂OC₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂OC₂H₅ Ph—8-(2)-thiophene 67 CH₂OC₂H₅ Ph— 9-methyl 68 CH₂OC₂H₅ Ph— 9-ethyl 69CH₂OC₂H₅ Ph— 9-iso-propyl 70 CH₂OC₂H₅ Ph— 9-tert-butyl 71 CH₂OC₂H₅ Ph—9-OH 72 CH₂OC₂H₅ Ph— 9-OCH₃ 73 CH₂OC₂H₅ Ph— 9-O(iso-propyl) 74 CH₂OC₂H₅Ph— 9-SCH₃ 75 CH₂OC₂H₅ Ph— 9-SOCH₃ 76 CH₂OC₂H₅ Ph— 9-SO₂CH₃ 77 CH₂OC₂H₅Ph— 9-SCH₂CH₃ 78 CH₂OC₂H₅ Ph— 9-NH₂ 79 CH₂OC₂H₅ Ph— 9-NHOH 80 CH₂OC₂H₅Ph— 9-NHCH₃ 81 CH₂OC₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂OC₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83CH₂OC₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂OC₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂OC₂H₅ Ph—9-NMeCH₂CO₂H 86 CH₂OC₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂OC₂H₅ Ph—9-(N)-morpholine 88 CH₂OC₂H₅ Ph— 9-(N)-azetidine 89 CH₂OC₂H₅ Ph—9-(N)-N-methylazetidinium, I⁻ 90 CH₂OC₂H₅ Ph— 9-(N)-pyrrolidine 91CH₂OC₂H₅ Ph— 9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂OC₂H₅ Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂OC₂H₅ Ph—9-(N)-N′-methylpiperazine 93 CH₂OC₂H₅ Ph— 9-(N)-N′-dimethylpiperazinium,I⁻ 95 CH₂OC₂H₅ Ph— 9-NH—CBZ 96 CH₂OC₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂OC₂H₅Ph— 9-NHC(O)CH₂Br 98 CH₂OC₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂OC₂H₅ Ph—9-(2)-thiophene 100 CH₂OC₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂OC₂H₅ Ph— 7-SCH₃,8-OCH₃ 102 CH₂OC₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂OC₂H₅ Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.010 01 CH₂CH(OH)C₂H₅ Ph— 7-methyl 02 CH₂CH(OH)C₂H₅ Ph—7-ethyl 03 CH₂CH(OH)C₂H₅ Ph— 7-iso-propyl 04 CH₂CH(OH)C₂H₅ Ph—7-tert-butyl 05 CH₂CH(OH)C₂H₅ Ph— 7-OH 06 CH₂CH(OH)C₂H₅ Ph— 7-OCH₃ 07CH₂CH(OH)C₂H₅ Ph— 7-O(iso-propyl) 08 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃ 09CH₂CH(OH)C₂H₅ Ph— 7-SOCH₃ 10 CH₂CH(OH)C₂H₅ Ph— 7-SO₂CH₃ 11 CH₂CH(OH)C₂H₅Ph— 7-SCH₂CH₃ 12 CH₂CH(OH)C₂H₅ Ph— 7-NH₂ 13 CH₂CH(OH)C₂H₅ Ph— 7-NHOH 14CH₂CH(OH)C₂H₅ Ph— 7-NHCH₃ 15 CH₂CH(OH)C₂H₅ Ph— 7-N(CH₃)₂ 16CH₂CH(OH)C₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂CH(OH)C₂H₅ Ph— 7-NHC(═O)CH₃ 18CH₂CH(OH)C₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂CH(OH)C₂H₅ Ph— 7-NMeCH₂CO₂H 20CH₂CH(OH)C₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂CH(OH)C₂H₅ Ph—7-(N)-morpholine 22 CH₂CH(OH)C₂H₅ Ph— 7-(N)-azetidine 23 CH₂CH(OH)C₂H₅Ph— 7-(N)-N-methylazetidinium, I⁻ 24 CH₂CH(OH)C₂H₅ Ph— 7-(N)-pyrrolidine25 CH₂CH(OH)C₂H₅ Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂CH(OH)C₂H₅Ph— 7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂CH(OH)C₂H₅ Ph—7-(N)-N′-methylpiperazine 28 CH₂CH(OH)C₂H₅ Ph—7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂CH(OH)C₂H₅ Ph— 7-NH—CBZ 30CH₂CH(OH)C₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂CH(OH)C₂H₅ Ph— 7-NHC(O)CH₂Br 32CH₂CH(OH)C₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂CH(OH)C₂H₅ Ph— 7-(2)-thiophene 34CH₂CH(OH)C₂H₅ Ph— 8-methyl 35 CH₂CH(OH)C₂H₅ Ph— 8-ethyl 36 CH₂CH(OH)C₂H₅Ph— 8-iso-propyl 37 CH₂CH(OH)C₂H₅ Ph— 8-tert-butyl 38 CH₂CH(OH)C₂H₅ Ph—8-OH 39 CH₂CH(OH)C₂H₅ Ph— 8-OCH₃ 40 CH₂CH(OH)C₂H₅ Ph— 8-O(iso-propyl) 41CH₂CH(OH)C₂H₅ Ph— 8-SCH₃ 42 CH₂CH(OH)C₂H₅ Ph— 8-SOCH₃ 43 CH₂CH(OH)C₂H₅Ph— 8-SO₂CH₃ 44 CH₂CH(OH)C₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂CH(OH)C₂H₅ Ph— 8-NH₂46 CH₂CH(OH)C₂H₅ Ph— 8-NHOH 47 CH₂CH(OH)C₂H₅ Ph— 8-NHCH₃ 48CH₂CH(OH)C₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂CH(OH)C₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50CH₂CH(OH)C₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂CH(OH)C₂H₅ Ph— 8-N(CH₂CH₃)₂ 52CH₂CH(OH)C₂H₅ Ph— 8-NMeCH₂CO₂H 53 CH₂CH(OH)C₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻54 CH₂CH(OH)C₂H₅ Ph— 8-(N)-morpholine 55 CH₂CH(OH)C₂H₅ Ph—8-(N)-azetidine 56 CH₂CH(OH)C₂H₅ Ph— 8-(N)-N-methylazetidinium, I⁻ 57CH₂CH(OH)C₂H₅ Ph— 8-(N)-pyrrolidine 58 CH₂CH(OH)C₂H₅ Ph—8-(N)-N-methyl-pyrrolidinium, I⁻ 59 CH₂CH(OH)C₂H₅ Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂CH(OH)C₂H₅ Ph—8-(N)-N′-methylpiperazine 61 CH₂CH(OH)C₂H₅ Ph—8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂CH(OH)C₂H₅ Ph— 8-NH—CBZ 63CH₂CH(OH)C₂H₅ PH— 8-NHC(O)C₅H₁₁ 64 CH₂CH(OH)C₂H₅ Ph— 8-NHC(O)CH₂Br 65CH₂CH(OH)C₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂CH(OH)C₂H₅ Ph— 8-(2)-thiophene 67CH₂CH(OH)C₂H₅ Ph— 9-methyl 68 CH₂CH(OH)C₂H₅ Ph— 9-ethyl 69 CH₂CH(OH)C₂H₅Ph— 9-iso-propyl 70 CH₂CH(OH)C₂H₅ Ph— 9-tert-butyl 71 CH₂CH(OH)C₂H₅ Ph—9-OH 72 CH₂CH(OH)C₂H₅ Ph— 9-OCH₃ 73 CH₂CH(OH)C₂H₅ Ph— 9-O(iso-propyl) 74CH₂CH(OH)C₂H₅ Ph— 9-SCH₃ 75 CH₂CH(OH)C₂H₅ Ph— 9-SOCH₃ 76 CH₂CH(OH)C₂H₅Ph— 9-SO₂CH₃ 77 CH₂CH(OH)C₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂CH(OH)C₂H₅ Ph— 9-NH₂79 CH₂CH(OH)C₂H₅ Ph— 9-NHOH 80 CH₂CH(OH)C₂H₅ Ph— 9-NHCH₃ 81CH₂CH(OH)C₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂CH(OH)C₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83CH₂CH(OH)C₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂CH(OH)C₂H₅ Ph— 9-N(CH₂CH₃)₂ 85CH₂CH(OH)C₂H₅ Ph— 9-NMeCH₂CO₂H 86 CH₂CH(OH)C₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻87 CH₂CH(OH)C₂H₅ Ph— 9-(N)-morpholine 88 CH₂CH(OH)C₂H₅ Ph—9-(N)-azetidine 89 CH₂CH(OH)C₂H₅ Ph— 9-(N)-N-methylazetidinium, I⁻ 90CH₂CH(OH)C₂H₅ Ph— 9-(N)-pyrrolidine 91 CH₂CH(OH)C₂H₅ Ph—9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂CH(OH)C₂H₅ Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂CH(OH)C₂H₅ Ph—9-(N)-N′-methylpiperazine 93 CH₂CH(OH)C₂H₅ Ph—9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂CH(OH)C₂H₅ Ph— 9-NH—CBZ 96CH₂CH(OH)C₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂CH(OH)C₂H₅ Ph— 9-NHC(O)CH₂Br 98CH₂CH(OH)C₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂CH(OH)C₂H₅ Ph— 9-(2)-thiophene 100CH₂CH(OH)C₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃, 8-OCH₃102 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂CH(OH)C₂H₅ Ph— 6-OCH₃,7-OCH₃, 8-OCH₃ F101.011 01 CH₂O-(4-picoline) Ph— 7-methyl 02CH₂O-(4-picoline) Ph— 7-ethyl 03 CH₂O-(4-picoline) Ph— 7-iso-propyl 04CH₂O-(4-picoline) Ph— 7-tert-butyl 05 CH₂O-(4-picoline) Ph— 7-OH 06CH₂O-(4-picoline) Ph— 7-OCH₃ 07 CH₂O-(4-picoline) Ph— 7-O(iso-propyl) 08CH₂O-(4-picoline) Ph— 7-SCH₃ 09 CH₂O-(4-picoline) Ph— 7-SOCH₃ 10CH₂O-(4-picoline) Ph— 7-SO₂CH₃ 11 CH₂O-(4-picoline) Ph— 7-SCH₂CH₃ 12CH₂O-(4-picoline) Ph— 7-NH₂ 13 CH₂O-(4-picoline) Ph— 7-NHOH 14CH₂O-(4-picoline) Ph— 7-NHCH₃ 15 CH₂O-(4-picoline) Ph— 7-N(CH₃)₂ 16CH₂O-(4-picoline) Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂O-(4-picoline) Ph—7-NHC(═O)CH₃ 18 CH₂O-(4-picoline) Ph— 7-N(CH₂CH₃)₂ 19 CH₂O-(4-picoline)Ph— 7-NMeCH₂CO₂H 20 CH₂O-(4-picoline) Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21CH₂O-(4-picoline) Ph— 7-(N)-morpholine 22 CH₂O-(4-picoline) Ph—7-(N)-azetidine 23 CH₂O-(4-picoline) Ph— 7-(N)-N-methylazetidinium, I⁻24 CH₂O-(4-picoline) Ph— 7-(N)-pyrrolidine 25 CH₂O-(4-picoline) Ph—7-(N)-N-methyl-pyrrolidinium, I⁻ 26 CH₂O-(4-picoline) Ph—7-(N)-N-methyl-morpholinium, I⁻ 27 CH₂O-(4-picoline) Ph—7-(N)-N′-methylpiperazine 28 CH₂O-(4-picoline) Ph—7-(N)-N′-dimethylpiperazinium, I⁻ 29 CH₂O-(4-picoline) Ph— 7-NH—CBZ 30CH₂O-(4-picoline) Ph— 7-NHC(O)C₅H₁₁ 31 CH₂O-(4-picoline) Ph—7-NHC(O)CH₂Br 32 CH₂O-(4-picoline) Ph— 7-NH—C(NH)NH₂ 33CH₂O-(4-picoline) Ph— 7-(2)-thiophene 34 CH₂O-(4-picoline) Ph— 8-methyl35 CH₂O-(4-picoline) Ph— 8-ethyl 36 CH₂O-(4-picoline) Ph— 8-iso-propyl37 CH₂O-(4-picoline) Ph— 8-tert-butyl 38 CH₂O-(4-picoline) Ph— 8-OH 39CH₂O-(4-picoline) Ph— 8-OCH₃ 40 CH₂O-(4-picoline) Ph— 8-O(iso-propyl) 41CH₂O-(4-picoline) Ph— 8-SCH₃ 42 CH₂O-(4-picoline) Ph— 8-SOCH₃ 43CH₂O-(4-picoline) Ph— 8-SO₂CH₃ 44 CH₂O-(4-picoline) Ph— 8-SCH₂CH₃ 45CH₂O-(4-picoline) Ph— 8-NH₂ 46 CH₂O-(4-picoline) Ph— 8-NHOH 47CH₂O-(4-picoline) Ph— 8-NHCH₃ 48 CH₂O-(4-picoline) Ph— 8-N(CH₃)₂ 49CH₂O-(4-picoline) Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂O-(4-picoline) Ph—8-NHC(═O)CH₃ 51 CH₂O-(4-picoline) Ph— 8-N(CH₂CH₃)₂ 52 CH₂O-(4-picoline)Ph— 8-NMeCH₂CO₂H 53 CH₂O-(4-picoline) Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54CH₂O-(4-picoline) Ph— 8-(N)-morpholine 55 CH₂O-(4-picoline) Ph—8-(N)-azetidine 56 CH₂O-(4-picoline) Ph— 8-(N)-N-methylazetidinium, I⁻57 CH₂O-(4-picoline) Ph— 8-(N)-pyrrolidine 58 CH₂O-(4-picoline) Ph—8-(N)-N-methyl-pyrrolidinium, I⁻ 59 CH₂O-(4-picoline) Ph—8-(N)-N-methyl-morpholinium, I⁻ 60 CH₂O-(4-picoline) Ph—8-(N)-N′-methylpiperazine 61 CH₂O-(4-picoline) Ph—8-(N)-N′-dimethylpiperazinium, I⁻ 62 CH₂O-(4-picoline) Ph— 8-NH—CBZ 63CH₂O-(4-picoline) Ph— 8-NHC(O)C₅H₁₁ 64 CH₂O-(4-picoline) Ph—8-NHC(O)CH₂Br 65 CH₂O-(4-picoline) Ph— 8-NH—C(NH)NH₂ 66CH₂O-(4-picoline) Ph— 8-(2)-thiophene 67 CH₂O-(4-picoline) Ph— 9-methyl68 CH₂O-(4-picoline) Ph— 9-ethyl 69 CH₂O-(4-picoline) Ph— 9-iso-propyl70 CH₂O-(4-picoline) Ph— 9-tert-butyl 71 CH₂O-(4-picoline) Ph— 9-OH 72CH₂O-(4-picoline) Ph— 9-OCH₃ 73 CH₂O-(4-picoline) Ph— 9-O(iso-propyl 74CH₂O-(4-picoline) Ph— 9-SCH₃ 75 CH₂O-(4-picoline) Ph— 9-SOCH₃ 76CH₂O-(4-picoline) Ph— 9-SO₂CH₃ 77 CH₂O-(4-picoline) Ph— 9-SCH₂CH₃ 78CH₂O-(4-picoline) Ph— 9-NH₂ 79 CH₂O-(4-picoline) Ph— 9-NHOH 80CH₂O-(4-picoline) Ph— 9-NHCH₃ 81 CH₂O-(4-picoline) Ph— 9-N(CH₃)₂ 82CH₂O-(4-picoline) Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂O-(4-picoline) Ph—9-NHC(═O)CH₃ 84 CH₂O-(4-picoline) Ph— 9-N(CH₂CH₃)₂ 85 CH₂O-(4-picoline)Ph— 9-NMeCH₂CO₂H 86 CH₂O-(4-picoline) Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87CH₂O-(4-picoline) Ph— 9-(N)-morpholine 88 CH₂O-(4-picoline) Ph—9-(N)-azetidine 89 CH₂O-(4-picoline) Ph— 9-(N)-N-methylazetidinium, I⁻90 CH₂O-(4-picoline) Ph— 9-(N)-pyrrolidine 91 CH₂O-(4-picoline) Ph—9-(N)-N-methyl-pyrrolidinium, I⁻ 92 CH₂O-(4-picoline) Ph—9-(N)-N-methyl-morpholinium, I⁻ 93 CH₂O-(4-picoline) Ph—9-(N)-N′-methylpiperazine 93 CH₂O-(4-picoline) Ph—9-(N)-N′-dimethylpiperazinium, I⁻ 95 CH₂O-(4-picoline) Ph— 9-NH—CBZ 96CH₂O-(4-picoline) Ph— 9-NHC(O)C₅H₁₁ 97 CH₂O-(4-picoline) Ph—9-NHC(O)CH₂Br 98 CH₂O-(4-picoline) Ph— 9-NH—C(NH)NH₂ 99CH₂O-(4-picoline) Ph— 9-(2)-thiophene 100 CH₂O-(4-picoline) Ph— 7-OCH₃,8-OCH₃ 101 CH₂O-(4-picoline) Ph— 7-SCH₃, 8-OCH₃ 102 CH₂O-(4-picoline)Ph— 7-SCH₃, 8-SCH₃ 103 CH₂O-(4-picoline) Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃

[0147] Additional Structures of the Present Invention

Compound Number R¹ R² R³ R⁴ R⁵ R⁶ (R″)_(q) 101 ethyl n-butyl OH H phenylH

102 ethyl n-butyl OH H phenyl H 7-trimethylammonium iodide 103 n-butylethyl OH H phenyl H 7-trimethylammonium iodide 104 ethyl n-butyl OH Hphenyl H 7-dimethylamino 105 ethyl n-butyl OH H phenyl H7-methanesulfonamido 106 ethyl n-butyl OH H phenyl H7-(2′-bromoacetamido) 107 n-butyl ethyl OH H 4-(decyloxy)phenyl H7-amino 108 ethyl n-butyl OH H phenyl H 7-(hexylamido) 109 ethyl n-butylOH H 4-(decyloxy)phenyl H 7-amino 110 ethyl n-butyl OH H phenyl H7-acetamido 111 n-butyl ethyl OH H 4-hydroxyphenyl H 7-amino 112 ethyln-butyl OH H

H 7-amino 113 ethyl n-butyl OH H 4-hydroxyphenyl H 7-amino 114 ethyln-butyl OH H 4-methoxyphenyl H 7-amino 115 n-butyl ethyl OH H4-methoxyphenyl H 7-(O-benzylcarbamato) 116 ethyl n-butyl OH H4-methoxyphenyl H 7-(O-benzylcarbamato) 117 n-butyl ethyl OH H phenyl H7-(O-benzylcarbamato) 118 ethyl n-butyl OH H phenyl H7-(O-benzylcarbamato) 119 ethyl n-butyl OH H phenyl H7-(O-tert-benzylcarbamato) 120 n-butyl ethyl OH H phenyl H7-(O-benzylcarbamato) 121 ethyl n-butyl OH H phenyl H 7-amino 122n-butyl ethyl OH H phenyl H 7-amino 123 ethyl n-butyl OH H phenyl H7-hexylamino 124 n-butyl ethyl OH H phenyl H 7-(hexylamino) 125 ethyln-butyl OH H phenyl H

126 n-butyl ethyl OH H 4-fluorophenyl H 7-(O-benzylcarbamato) 127n-butyl ethyl OH H 4-fluorophenyl H 7-amino 128 ethyl n-butyl OH H4-fluorophenyl H 7-(O-benzylcarbamato) 129 ethyl n-butyl OH H4-fluorophenyl H 7-amino 131 ethyl n-butyl OH H 4-fluorophenyl H

132 ethyl n-butyl OH H phenyl H

133 ethyl n-butyl OH H phenyl H 8-(hexyloxy) 134 ethyl n-butyl OH Hphenyl H

135 ethyl n-butyl OH H phenyl H

136 ethyl n-butyl OH H phenyl H 8-hydroxy 137 n-butyl ethyl OH H phenylH

138 n-butyl ethyl OH H phenyl H 8-acetoxy 139 n-butyl ethyl OH H phenylH

142 ethyl n-butyl H OH H 3-methoxy- 7-methylmercapto phenyl 143 ethyln-butyl OH H 3-methoxyphenyl H 7-methylmercapto 144 ethyl n-butyl OH H4-fluorophenyl H 7-(N-azetidinyl) 262 ethyl n-butyl OH H3-methtoxyphenyl H 7-methoxy 263 ethyl n-butyl H OH H 3-methoxy-7-methoxy phenyl 264 ethyl n-butyl OH H 3-trifluoromethylphenyl H7-methoxy 265 ethyl n-butyl H OH H 3-trifluoro- 7-methoxy methyl- phenyl266 ethyl n-butyl OH H 3-hydroxyphenyl H 7-hydroxy 267 ethyl n-butyl OHH 3-hydroxyphenyl H 7-methoxy 268 ethyl n-butyl OH H 4-fluorophenyl H7-methoxy 269 ethyl n-butyl H OH H 4-fluoro- 7-methoxy phenyl 270 ethyln-butyl OH H 4-fluorophenyl H 7-hydroxy 271 ethyl n-butyl OH H3-methoxyphenyl H 7-bromo 272 ethyl n-butyl H OH H 3-methoxy- 7-bromophenyl 273 ethyl n-butyl H OH H 4-fluoro- 7-fluoro phenyl 274 ethyln-butyl OH H 4-fluorophenyl H 7-fluoro 275 ethyl n-butyl H OH H3-methoxy- 7-fluoro phenyl 276 ethyl n-butyl OH H 3-methoxyphenyl H7-fluoro 277 ethyl n-butyl OH H 3-fluorophenyl H 7-methoxy 278 ethyln-butyl H OH 2-fluorophenyl H 7-methoxy 279 ethyl n-butyl H OH3-fluorophenyl H 7-methoxy 280 ethyl n-butyl OH H 2-fluorophenyl H7-methoxy 281 ethyl n-butyl OH H 4-fluorophenyl H 7-methylmercapto 282ethyl n-butyl OH H 4-fluorophenyl H 7-methyl 283 ethyl n-butyl H OH H4-fluoro- 7-methyl phenyl 284 ethyl n-butyl OH H 4-fluorophenyl H7-(4′-morpholino) 285 OH H MISSING 286 ethyl ethyl OH H phenyl H7-(O-benzylcarbamato) 287 ethyl ethyl OH H phenyl H 7-amino 288 methylmethyl OH H phenyl H 7-amino 289 n-butyl n-butyl OH H phenyl H 7-amino290 n-butyl n-butyl OH H phenyl H 7-amino 291 n-butyl n-butyl OH Hphenyl H 7-(O-benzylcarbamato) 292 n-butyl n-butyl OH H 4-fluorophenyl H7-amino 293 n-butyl n-butyl OH H phenyl H 7-benzylamino 294 n-butyln-butyl OH H phenyl H 7-dimethylamino 295 ethyl n-butyl OH H

H 7-amino 296 ethyl n-butyl OH H

H 7-amino 1000 ethyl n-butyl OH H

H 7-dimethylamino 1001 ethyl n-butyl OH H

H 7-dimethylamino 1002 ethyl n-butyl OH H

H 7-dimethylamino 1003 ethyl n-butyl OH H

H 7-dimethylamino 1004 ethyl n-butyl OH H

H 7-dimethylamino 1005 n-butyl n-butyl OH H

H 7-dimethylamino 1006 n-butyl n-butyl OH H

H 7-dimethylamino 1007 n-butyl n-butyl OH H

H 7-dimethylamino 1008 n-butyl n-butyl OH H

H 7-dimethylamino 1009 n-butyl n-butyl OH H

H 7-dimethylamino 1010 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H7-dimethylamino 1011 n-butyl n-butyl OH H3-fluoro-4-(5-triethylammoniumpentyloxy)phenyl, H 7-dimethylaminotrifluoroacetate salt 1012 n-butyl n-butyl OH H 4-hydroxyphenyl H7-dimethylamino; 9-methoxy 1013 n-butyl n-butyl OH H

H 7-dimethylamino 1014 n-butyl n-butyl OH H 4-methoxyphenyl H7-dimethylamino; 9-methoxy 1015 n-butyl n-butyl OH H

H 7-dimethylamino 1016 n-butyl n-butyl OH H

H 7-dimethylamino 1017 n-butyl n-butyl OH H

H 7-dimethylamino 1018 n-butyl n-butyl OH H

H 7-dimethylamino 1019 n-butyl n-butyl OH H

H 7-dimethylamino 1020 n-butyl n-butyl OH H

H 7-dimethylamino 1021 n-butyl n-butyl OH H

H 7-dimethylamino 1022 n-butyl n-butyl OH H

H 7-dimethylamino 1023 n-butyl n-butyl OH H

H 7-dimethylamino 1024 n-butyl n-butyl OH H

H 7-dimethylamino 1025 n-butyl n-butyl OH H

H 7-dimethylamino 1026 n-butyl n-butyl OH H

H 7-dimethylamino 1027 n-butyl n-butyl OH H

H 7-dimethylamino 1028 n-butyl n-butyl OH H

H 7-dimethylamino 1029 n-butyl n-butyl OH H

H 7-dimethylamino 1030 n-butyl n-butyl OH H

H 7-dimethylamino 1031 n-butyl n-butyl OH H

H 7-dimethylamino 1032 n-butyl n-butyl OH H

H 7-dimethylamino 1033 n-butyl n-butyl OH H

H 7-dimethylamino 1034 n-butyl n-butyl OH H

H 7-dimethylamino 1035 n-butyl n-butyl OH H

H 7-dimethylamino 1036 n-butyl n-butyl OH H

H 7-dimethylamino 1037 n-butyl n-butyl OH H 4-hydroxyphenyl H7-dimethylamino 1038 n-butyl n-butyl OH H

H 7-dimethylamino 1039 n-butyl n-butyl OH H phenyl H 7-dimethylamino1040 n-butyl n-butyl OH H

H 7-dimethylamino 1041 n-butyl n-butyl OH H

H 7-dimethylamino 1042 n-butyl n-butyl OH H

H 7-dimethylamino 1043 n-butyl n-butyl OH H

H 7-dimethylamino 1044 n-butyl n-butyl OH H

H 7-dimethylamino 1045 n-butyl n-butyl OH H

H 7-dimethylamino 1046 n-butyl n-butyl OH H 3-aminophenyl H7-dimethylamino 1047 n-butyl n-butyl OH H

H 7-dimethylamino 1048 n-butyl n-butyl OH H

H 7-dimethylamino 1049 n-butyl n-butyl OH H

H 7-dimethylamino 1050 n-butyl n-butyl OH H

H 7-dimethylamino 1051 n-butyl n-butyl OH H

H 7-dimethylamino 1052 n-butyl n-butyl OH H

H 7-dimethylamino 1053 n-butyl n-butyl OH H

H 7-dimethylamino 1054 n-butyl n-butyl OH H

H 7-dimethylamino 1055 n-butyl n-butyl OH H

H 7-dimethylamino 1056 n-butyl n-butyl OH H

H 7-dimethylamino 1057 n-butyl n-butyl OH H

H 7-dimethylamino 1058 n-butyl n-butyl OH H

H 7-dimethylamino 1059 n-butyl n-butyl OH H

H 7-dimethylamino 1060 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl H7-methylamino 1061 n-butyl n-butyl OH H

H 7-methylamino 1062 n-butyl n-butyl OH H

H 7-methylamino 1063 n-butyl n-butyl OH H

H 7-methylamino 1064 n-butyl n-butyl OH H

H 7-methylamino 1065 n-butyl n-butyl OH H

H 7-dimethylamino 1066 n-butyl n-butyl OH H

H 7-dimethylamino 1067 n-butyl n-butyl OH H thiophen-3-yl H9-dimethylamino 1068 n-butyl n-butyl OH H

H 7-dimethylamino 1069 n-butyl n-butyl OH H phenyl H 7-dimethylamino;9-dimethylamino 1070 n-butyl n-butyl OH H

H 7-dimethylamino 1071 n-butyl n-butyl OH H

H 7-dimethylamino 1072 n-butyl n-butyl OH H

H 7-dimethylamino 1073 n-butyl n-butyl OH H

H 7-dimethylamino 1074 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl H7-dimethylamino 1075 n-butyl n-butyl OH H 4-fluorophenyl H7-dimethylamino; 9-dimethylamino 1076 n-butyl n-butyl OH H

H 7-dimethylamino 1077 n-butyl n-butyl OH H 3-hydroxymethylphenyl H7-dimethylamino 1078 ethyl n-butyl OH H 4-hydroxyphenyl H7-dimethylamino 1079 ethyl n-butyl OH H

H 7-dimethylamino 1080 n-butyl n-butyl OH H

H 7-dimethylamino 1081 n-butyl n-butyl OH H

H 7-dimethylamino 1082 n-butyl n-butyl OH H 2-pyridyl H 7-dimethylamino1083 n-butyl n-butyl OH H

H 7-dimethylamino 1084 n-butyl n-butyl OH H

H 7-dimethylamino 1085 n-butyl n-butyl OH H thiophen-3-yl H7-dimethylamino 1086 n-butyl n-butyl OH H

H 7-dimethylamino 1087 n-butyl n-butyl OH H

H 7-dimethylamino 1088 ethyl n-butyl OH H 3,4-methylenedioxyphenyl H7-dimethylamino 1089 ethyl n-butyl OH H 4-methoxyphenyl H7-dimethylamino 1090 n-butyl n-butyl OH H

H 7-dimethylamino 1091 n-butyl n-butyl OH H

H 7-dimethylamino 1092 n-butyl n-butyl OH H

H 7-dimethylamino 1093 n-butyl n-butyl OH H

H 7-dimethylamino 1094 n-butyl n-butyl OH H

H 7-dimethylamino 1095 n-butyl n-butyl OH H

H 7-dimethylamino 1096 n-butyl n-butyl OH H

H 7-dimethylamino 1097 n-butyl n-butyl OH H

H 7-dimethylamino 1098 n-butyl n-butyl OH H

H 7-dimethylamino 1099 ethyl n-butyl OH H 4-methoxyphenyl H7-dimethylamino 1100 n-butyl n-butyl OH H 4-methoxyphenyl H7-dimethylamino 1101 n-butyl n-butyl OH H

H 7-dimethylamino 1102 n-butyl n-butyl OH H 3-carboxymethylphenyl H7-dimethylamino 1103 n-butyl n-butyl OH H

H 7-dimethylamino 1104 n-butyl n-butyl OH H

H 7-dimethylamino 1105 n-butyl n-butyl OH H 5-piperonyl H7-dimethylamino 1106 n-butyl n-butyl OH H 3-hydroxyphenyl H7-dimethylamino 1107 n-butyl n-butyl OH H

H 7-dimethylamino 1108 n-butyl n-butyl OH H 3-pyridyl H 7-dimethylamino1109 n-butyl n-butyl OH H

H 7-dimethylamino 1110 n-butyl n-butyl OH H

H 7-dimethylamino 1111 n-butyl n-butyl OH H

H 7-dimethylamino 1112 n-butyl n-butyl OH H 4-pyridyl H 7-dimethylamino1113 n-butyl n-butyl OH H

H 7-dimethylamino 1114 n-butyl n-butyl OH H 3-methoxyphenyl H7-methylamino 1115 n-butyl n-butyl OH H 4-fluorophenyl H 7-dimethylamino1116 ethyl n-butyl OH H 3-tolyl H 7-dimethylamino 1117 ethyl n-butyl OHH

H 7-dimethylamino 1118 ethyl n-butyl OH H 3-fluoro-4-hydroxyphenyl H7-dimethylamino 1119 n-butyl n-butyl OH H

H 7-dimethylamino 1120 n-butyl n-butyl OH H

H 7-dimethylamino 1121 n-butyl n-butyl OH H

H 7-dimethylamino 1122 n-butyl n-butyl OH H

H 7-dimethylamino 1123 n-butyl n-butyl OH H phenyl H 7-dimethylamino1124 n-butyl n-butyl OH H 3-methoxyphenyl H 7-dimethylamino 1125 n-butyln-butyl OH H 3-chloro-4-methoxyphenyl H 7-dimethylamino 1126 ethyln-butyl OH H

H 7-dimethylamino 1127 n-butyl n-butyl OH H

H 7-dimethylamino 1128 n-butyl n-butyl OH H 3-fluoro-4-hydroxyphenyl H7-dimethylamino 1129 n-butyl n-butyl OH H 4-fluorophenyl H9-dimethylamino 1130 n-butyl n-butyl OH H 3-chloro-4-fluorophenyl H7-dimethylamino 1131 ethyl n-butyl OH H 4-methoxyphenyl H7-dimethylamino 1132 n-butyl n-butyl OH H

H 7-dimethylamino 1133 n-butyl n-butyl OH H 4-cyanomethylphenyl H7-dimethylamino 1134 ethyl n-butyl OH H

H 7-dimethylamino 1135 n-butyl n-butyl OH H 3,4-dimethoxyphenyl H7-dimethylamino 1136 n-butyl n-butyl OH H

H 7-dimethylamino 1137 n-butyl n-butyl OH H 4-fluorophenyl H9-(2′,2′-dimethylhydrazino) 1138 n-butyl n-butyl OH H

H 7-dimethylamino 1139 n-butyl n-butyl OH H 3,4-difluorophenyl H7-dimethylamino 1140 n-butyl n-butyl OH H 3-methoxyphenyl H7-(2′,2′-dimethylhydrazino) 1141 n-butyl n-butyl OH H 4-fluorophenyl H7-dimethylamino 1142 n-butyl n-butyl OH H

H 7-dimethylamino 1143 n-butyl n-butyl H OH H 3-fluoro-4-7-dimethylamino methoxy- phenyl 1144 n-butyl n-butyl OH H 5-piperonyl H7-dimethylamino 1145 n-butyl n-butyl OH H 4-methoxyphenyl H9-dimethylamino 1146 n-butyl n-butyl OH H

H 7-dimethylamino 1147 n-butyl n-butyl OH H 3-methoxyphenyl H7-diethylamino 1148 n-butyl n-butyl OH H 4-fluorophenyl H4-dimethylsulfonium, fluoride salt 1149 n-butyl n-butyl OH H4-fluorophenyl H 7-ethylamino 1150 n-butyl n-butyl OH H 3-methoxyphenylH 7-ethylmethylamino 1151 n-butyl ethyl OH H 3-fluoro-4-methoxyphenyl H7-dimethylamino 1152 n-butyl n-butyl OH H phenyl H7-(ethoxymethyl)methylamino 1153 n-butyl n-butyl OH H 4-fluorophenyl H7-methylamino 1154 n-butyl n-butyl OH H 3-methoxyphenyl H 9-methoxy 1155n-butyl n-butyl OH H 4-fluorophenyl H 7-methyl 1156 n-butyl n-butyl OH H4-fluorophenyl H 7-methylmercapto 1157 n-butyl n-butyl OH H4-fluorophenyl H 7-fluoro; 9-dimethylamino 1158 n-butyl n-butyl OH H4-pyridinyl, hydrochloride salt H 7-methoxy 1159 n-butyl ethyl OH Hphenyl H 7-dimethylamino 1160 n-butyl n-butyl OH H 4-fluorophenyl H7-diethylamino 1161 n-butyl n-butyl OH H 3,5-dichloro-4-methoxyphenyl H7-dimethylamino 1162 n-butyl n-butyl OH H phenyl H 7-dimethylamino 1163n-butyl n-butyl OH H 3-(dimethylamino)phenyl H 7-methoxy 1164 n-butyln-butyl OH H 4-pyridinyl H 7-methoxy 1165 n-butyl n-butyl OH H3-fluoro-4-methoxyphenyl H 7-trimethylammonium iodide 1166 n-butyln-butyl OH H 3-hydroxyphenyl H 7-trimethylammonium iodide 1167 n-butyln-butyl OH H

H 7-dimethylamino 1168 n-butyl n-butyl OH H 4-hydroxyphenyl H7-trimethylammonium iodide 1169 n-butyl n-butyl OH H phenyl H8-dimethylamino 1170 n-butyl n-butyl OH H 3-methoxyphenyl H7-ethylpropylamino 1171 n-butyl n-butyl OH H4-(trifluoromethylsulfonyloxy)phenyl H 7-dimethylamino 1172 n-butyln-butyl OH H 4-pyridinyl H 7-methoxy 1173 n-butyl n-butyl OH H4-fluorophenyl H 7-ethylpropylamino 1174 ethyl n-butyl OH H3-methoxyphenyl H 7-phenyl 1175 ethyl n-butyl OH H 3-methoxyphenyl H7-methylsulfonyl 1176 n-butyl n-butyl OH H 4-fluorophenyl H 9-fluoro1177 n-butyl n-butyl OH H 3-methoxyphenyl H 7-butylmethylamino 1178n-butyl n-butyl OH H 3-(trifluoromethylsulfonyloxy)phenyl H7-dimethylamino 1179 n-butyl n-butyl OH H phenyl H 8-methoxy 1180n-butyl n-butyl OH H phenyl H 7-trimethylammonium iodide 1181 n-butyln-butyl OH H 4-fluorophenyl H 7-butylmethylamino 1182 n-butyl n-butyl OHH 4-(dimethylamino)phenyl H 7-methoxy 1183 n-butyl n-butyl OH H3-methoxyphenyl H 7-fluoro 1184 n-butyl n-butyl OH H 4-fluorophenyl H7-fluoro; 9-fluoro 1185 n-butyl n-butyl OH H 4-fluorophenyl H 7-fluoro1186 n-butyl n-butyl OH H phenyl H 7-fluoro; 9-fluoro 1187 n-butyln-butyl OH H 4-fluorophenyl H 7-methyl 1188 n-butyl n-butyl OH H4-methoxyphenyl H 7-trimethylammonium iodide 1189 n-butyl n-butyl OH H3,4-difluorophenyl H 7-trimethylammonium iodide 1190 n-butyl n-butyl OHH 2-bromophenyl H 7-bromo 1191 n-butyl n-butyl OH H4-(dimethylamino)phenyl H 7-hydroxy 1192 n-butyl n-butyl OH H3-(dimethylamino)phenyl H 7-hydroxy 1193 n-butyl n-butyl OH H4-(2-(2-methylpropyl)phenyl H 7-dimethylamino 1194 n-butyl n-butyl OH H

H 7-dimethylamino 1195 n-butyl n-butyl OH H 4-methoxyphenyl H7-(4′-methylpiperazin-1-yl) 1196 n-butyl n-butyl OH H

H 7-methoxy 1197 n-butyl ethyl R3 + R3 + phenyl H 7-(N-methylformamido)R4 = R4 = oxo oxo 1198 n-butyl n-butyl OH H 4-(pyridinyl-N-oxide) H7-methoxy 1199 n-butyl n-butyl OH H

H 7-dimethylamino 1200 n-butyl n-butyl H OH H phenyl 7-dimethylamino1201 n-butyl n-butyl OH H H H 7-methyl 1202 n-butyl n-butyl OH H

H 7-methoxy 1203 n-butyl n-butyl OH H 5-piperazinyl H7-(4′-tert-butylphenyl) 1204 n-butyl n-butyl OH H 4-fluorophenyl H7-methoxy 1205 n-butyl n-butyl OH H

H 7-dimethylamino 1206 n-butyl n-butyl OH H

H 7-dimethylamino 1207 n-butyl n-butyl OH H 3,5-dichlorophenyl H7-dimethylamino 1208 n-butyl n-butyl OH H 4-methoxyphenyl H7-dimethylamino 1209 n-butyl n-butyl acetoxy H phenyl H 7-dimethylphenyl1210 n-butyl n-butyl OH H 2-(dimethylamino)phenyl H 7-dimethylamino 1211ethyl n-butyl OH H

H 7-dimethylamino 1212 n-butyl n-butyl OH H 4-methoxyphenyl H9-(4′-morpholino) 1213 n-butyl ethyl H OH H 3-fluoro-4- 7-dimethylaminomethoxy- phenyl 1214 n-butyl ethyl OH H phenyl H 7-(N-methylformamido)1215 n-butyl n-butyl OH H 4-methoxyphenyl H 9-methylmercapto 1216 ethyln-butyl OH H 5-piperonyl H 7-bromo 1217 n-butyl n-butyl OH H4-carboxyphenyl H 7-dimethylamino 1218 n-butyl n-butyl OH H4-methoxyphenyl H 9-methylsulfonyl 1219 n-butyl n-butyl OH H

H 7-dimethylamino 1220 n-butyl n-butyl OH H 3-methoxyphenyl H7-isopropylamino 1221 n-butyl n-butyl OH H

H 7-dimethylamino 1222 n-butyl n-butyl OH H 3-methoxyphenyl H7-ethylamino 1223 n-butyl n-butyl OH H phenyl H 8-bromo; 7-methylamino1224 n-butyl n-butyl OH H 3-nitrophenyl H 7-fluoro 1225 n-butyl ethyl OHH 3-methylphenyl H 7-dimethylamino 1226 ethyl n-butyl OH H 5-piperonyl H7-bromo 1227 n-butyl n-butyl OH H 4-fluorophenyl H 7-(tert-butylamino1228 n-butyl n-butyl OH H 2-pyrrolyl H 8-bromo; 7-dimethylamino 1229n-butyl n-butyl OH H 3-chloro-4-hydroxyphenyl H 7-dimethylamino 1230n-butyl n-butyl OH H phenyl H 9-dimethylamino; 7-fluoro 1231 n-butyln-butyl OH H

H 7-dimethylamino 1232 n-butyl n-butyl H OH 3-thiophenyl H9-dimethylamino 1233 n-butyl n-butyl OH H

H 7-dimethylamino 1234 n-butyl n-butyl OH H

H 7-dimethylamino 1235 n-butyl n-butyl OH H

H 7-dimethylamino 1236 n-butyl n-butyl OH H 4-(bromomethyl)phenyl H7-dimethylamino 1237 n-butyl n-butyl OH H

H 7-dimethylamino 1238 n-butyl n-butyl OH H

H 7-dimethylamino 1239 n-butyl n-butyl OH H

H 7-dimethylamino 1240 n-butyl n-butyl OH H 4-methoxy-3-methylphenyl H7-dimethylamino 1241 n-butyl n-butyl OH H 3-(dimethylaminomethyl)phenylH 7-dimethylamino 1242 n-butyl n-butyl OH H

H 7-dimethylamino 1243 n-butyl n-butyl OH H

H 7-dimethylamino 1244 n-butyl n-butyl OH H 3-methoxyphenyl H7-(1′-methylhydrazido) 1245 n-butyl n-butyl OH H

H 7-dimethylamino 1246 n-butyl n-butyl OH H 3-(bromomethyl)phenyl H7-dimethylamino 1247 n-butyl n-butyl OH H

H 7-dimethylamino 1248 n-butyl n-butyl OH H

H 7-dimethylamino 1249 n-butyl n-butyl OH H

H 7-dimethylamino 1250 n-butyl n-butyl OH H 3-(dimethylamino)phenyl H7-dimethylamino 1251 n-butyl n-butyl OH H 1-naphthyl H 7-dimethylamino1252 n-butyl n-butyl OH H

H 7-dimethylamino 1253 n-butyl n-butyl OH H

H 7-dimethylamino 1254 n-butyl n-butyl OH H

H 7-dimethylamino 1255 n-butyl n-butyl OH H

H 7-dimethylamino 1256 n-butyl n-butyl OH H 3-nitrophenyl H7-dimethylamino 1257 n-butyl n-butyl OH H phenyl H 8-bromo;7-dimethylamino 1258 n-butyl n-butyl OH H 4-fluorophenyl H9-(tert-butylamino) 1259 ethyl n-butyl H OH H phenyl 7-dimethylamino1260 ethyl n-butyl OH H 3-hydroxyphenyl H 7-dimethylamino 1261 n-butyln-butyl OH H

H 7-dimethylamino 1262 n-butyl n-butyl OH H 2-thiophenyl H7-dimethylamino 1263 n-butyl n-butyl OH H 5-piperonyl H 7-bromo 1264n-butyl n-butyl OH H 4-fluorophenyl H 7-isopropylamino 1265 n-butyln-butyl OH H 4-fluorophenyl H 9-isopropylamino 1266 n-butyl n-butyl OH H

H 7-dimethylamino 1267 n-butyl ethyl OH H 5-piperonyl H 7-carboxy,methyl ester 1268 n-butyl n-butyl OH H

H 7-dimethylamino 1269 n-butyl n-butyl OH H

H 7-dimethylamino 1270 n-butyl n-butyl OH H

H 7-dimethylamino 1271 n-butyl n-butyl OH H

H 7-dimethylamino 1272 n-butyl n-butyl OH H

H 7-dimethylamino 1273 n-butyl n-butyl OH H

H 7-dimethylamino 1274 n-butyl n-butyl OH H

H 7-dimethylamino 1275 n-butyl n-butyl OH H

H 7-dimethylamino 1276 n-butyl n-butyl OH H

H 7-dimethylamino 1277 n-butyl n-butyl OH H

H 7-dimethylamino 1278 n-butyl n-butyl OH H

H 7-dimethylamino 1279 n-butyl n-butyl OH H

H 7-dimethylamino 1280 n-butyl n-butyl OH H

H 7-dimethylamino 1281 n-butyl n-butyl OH H

H 7-dimethylamino 1282 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl H7-trimethylammonium iodide 1283 n-butyl n-butyl OH H4-hydroxymethylphenyl H 7-dimethylamino 1284 n-butyl n-butyl OH H4-fluorophenyl H 9-ethylamino 1285 n-butyl ethyl OH H phenyl H7-dimethylamino 1286 n-butyl n-butyl OH H

H 7-dimethylamino 1287 n-butyl ethyl OH H 4-hydroxyphenyl H7-dimethylamino 1288 n-butyl n-butyl OH H

H 7-dimethylamino 1289 n-butyl n-butyl OH H

H 7-dimethylamino 1290 n-butyl n-butyl OH H

H 7-dimethylamino 1291 n-butyl n-butyl OH H

H 7-dimethylamino 1292 n-butyl n-butyl OH H

H 7-dimethylamino 1293 n-butyl n-butyl OH H

H 7-dimethylamino 1294 n-butyl n-butyl OH H

H 7-dimethylamino 1295 n-butyl n-butyl OH H

H 7-dimethylamino 1296 n-butyl n-butyl OH H

H 7-dimethylamino 1297 n-butyl n-butyl OH H

H 7-dimethylamino 1298 n-butyl n-butyl OH H

H 7-dimethylamino 1299 n-butyl n-butyl OH H

H 7-dimethylamino 1300 n-butyl ethyl H OH H phenyl 7-dimethylamino 1301n-butyl n-butyl OH H 3-methoxyphenyl H 7-trimethylammonium iodide 1302n-butyl n-butyl OH H 3-hydroxyphenyl H 9-hydroxy 1303 n-butyl n-butyl OHH

H 7-dimethylamino 1304 n-butyl n-butyl OH H 3-methoxyphenyl H7-tert-butylamino 1305 n-butyl n-butyl OH H 4-fluorophenyl H9-methylamino 1306 n-butyl n-butyl OH H

H 7-dimethylamino 1307 n-butyl n-butyl OH H H 4-methoxy-9-(4′-morpholino) phenyl 1308 ethyl n-butyl OH H

H 7-dimethylamino 1309 n-butyl n-butyl OH H 4-methoxyphenyl H 9-fluoro1310 ethyl n-butyl OH H phenyl H 7-amino 1311 n-butyl ethyl OH H phenylH 7-(hydroxyamino) 1312 n-butyl ethyl OH H phenyl H 8-hexyloxy 1313n-butyl ethyl OH H phenyl H 8-ethoxy 1314 ethyl n-butyl OH H phenyl H7-(hydroxylamino) 1315 ethyl n-butyl OH H phenyl H 7-(hexyloxy) 1316n-butyl ethyl OH H phenyl H 8-hydroxy 1317 n-butyl ethyl OH H phenyl H

1318 ethyl n-butyl OH H phenyl H 7-dimethylamino 1319 ethyl n-butyl OH H3-methoxyphenyl H 7-fluoro 1320 ethyl n-butyl OH H phenyl H 7-amino 1321n-butyl ethyl OH H phenyl H

1322 n-butyl n-butyl OH H

H 7-dimethylamino 1323 n-butyl n-butyl OH H

H 7-dimethylamino 1324 n-butyl n-butyl OH H

H 7-dimethylamino 1325 n-butyl n-butyl OH H4-((diethylamino)methyl)phenyl H 7-dimethylamino 1326 n-butyl n-butyl OHH

H 7-dimethylamino 1327 n-butyl n-butyl OH H3-fluoro-4-hydroxy-5-iodophenyl H 7-dimethylamino 1328 n-butyl n-butylOH H

H 7-dimethylamino 1329 n-butyl n-butyl OH H

H 7-dimethylamino 1330 n-butyl n-butyl OH H

H 7-dimethylamino 1331 n-butyl n-butyl OH H

H 7-dimethylamino 1332 n-butyl n-butyl OH H

H 7-dimethylamino 1333 n-butyl n-butyl OH H

H 7-dimethylamino 1334 n-butyl n-butyl OH H

H 7-dimethylamino 1335 n-butyl n-butyl OH H

H 7-dimethylamino 1336 n-butyl n-butyl OH H

H 7-dimethylamino 1337 n-butyl n-butyl OH H

H 7-dimethylamino 1338 n-butyl n-butyl OH H 4-methoxyphenyl H7-(4′-methylpiperazinyl) 1339 n-butyl n-butyl OH H

H 7-dimethylamino 1340 n-butyl ethyl OH H 5-piperonyl H 7-methyl 1341n-butyl n-butyl acetoxy H 3-methoxyphenyl H 7-dimethylamino 1342 n-butyln-butyl OH H 5-piperonyl H 7-(4′-fluoroamino) 1343 ethyl n-butyl OH Hphenyl H 7-amino 1344 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H7-dimethylamino 1345 ethyl n-butyl OH H phenyl H 7-trimethylammoniumiodide 1346 ethyl n-butyl OH H phenyl H

1347 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino1348 isobutyl isobutyl OH H phenyl H 7-dimethylamino 1349 ethyl n-butylOH H phenyl H 7-dimethylamino 1350 n-butyl n-butyl OH H3-fluoro-4-methoxyphenyl H 7-trimethylammonium iodide 1351 n-butyln-butyl OH H

H 7-dimethylamino 1352 n-butyl n-butyl OH H

H 7-dimethylamino 1353 n-butyl n-butyl OH H

H 7-dimethylamino 1354 n-butyl n-butyl OH H

H 7-dimethylamino 1355 n-butyl n-butyl OH H

H 7-dimethylamino 1356 n-butyl n-butyl OH H

H 7-dimethylamino 1357 n-butyl n-butyl OH H

H 7-dimethylamino 1358 n-butyl n-butyl OH H

H 7-dimethylamino 1359 n-butyl n-butyl OH H

H 7-dimethylamino 1360 n-butyl n-butyl OH H

H 7-dimethylamino 1361 n-butyl n-butyl OH H

H 7-dimethylamino 1362 n-butyl n-butyl OH H

H 7-dimethylamino 1363 n-butyl n-butyl OH H

H 7-dimethylamino 1364 n-butyl n-butyl OH H

H 7-dimethylamino 1365 n-butyl n-butyl OH H

H 7-dimethylamino 1366 n-butyl n-butyl OH H

H 7-dimethylamino 1367 n-butyl n-butyl OH H

H 7-dimethylamino 1368 n-butyl n-butyl OH H

H 7-dimethylamino 1369 n-butyl n-butyl OH H

H 7-dimethylamino 1370 n-butyl n-butyl OH H

H 7-dimethylamino 1371 n-butyl n-butyl OH H

H 7-dimethylamino 1372 n-butyl n-butyl OH H

H 7-dimethylamino 1373 n-butyl n-butyl OH H

H 7-dimethylamino 1374 n-butyl n-butyl OH H

H 7-dimethylamino 1375 n-butyl n-butyl OH H

H 7-dimethylamino 1376 n-butyl n-butyl OH H

H 7-dimethylamino 1377 n-butyl n-butyl OH H

H 7-dimethylamino 1378 n-butyl n-butyl OH H

H 7-dimethylamino 1379 n-butyl n-butyl OH H

H 7-dimethylamino 1380 n-butyl n-butyl OH H

H 7-dimethylamino 1381 n-butyl n-butyl OH H

H 7-dimethylamino 1382 n-butyl n-butyl OH H

H 7-dimethylamino 1383 n-butyl n-butyl OH H

H 7-dimethylamino 1384 n-butyl n-butyl OH H

H 7-dimethylamino 1385 n-butyl n-butyl OH H

H 7-dimethylamino 1386 n-butyl n-butyl OH H

H 7-dimethylamino 1387 n-butyl n-butyl OH H

H 7-dimethylamino 1388 n-butyl n-butyl OH H

H 7-dimethylamino 1389 n-butyl n-butyl OH H

H 7-dimethylamino 1390 n-butyl n-butyl OH H

H 7-dimethylamino 1391 n-butyl n-butyl OH H

H 7-dimethylamino 1392 n-butyl n-butyl OH H

H 7-dimethylamino 1393 n-butyl n-butyl OH H

H 7-dimethylamino 1394 n-butyl n-butyl OH H

H 7-dimethylamino 1395 n-butyl n-butyl OH H

H 7-dimethylamino 1396 n-butyl n-butyl OH H

H 7-dimethylamino 1397 n-butyl n-butyl OH H

H 7-dimethylamino 1398 n-butyl n-butyl OH H

H 7-dimethylamino 1399 n-butyl n-butyl OH H

H 7-dimethylamino 1400 n-butyl n-butyl OH H

H 7-dimethylamino 1401 n-butyl n-butyl OH H

H 7-dimethylamino 1402 n-butyl n-butyl OH H

H 7-dimethylamino 1403 n-butyl n-butyl OH H

H 7-dimethylamino 1404 n-butyl n-butyl OH H

H 7-dimethylamino 1405 n-butyl n-butyl OH H

H 7-dimethylamino 1406 n-butyl n-butyl OH H

H 7-dimethylamino 1407 n-butyl n-butyl OH H

H 7-dimethylamino 1408 n-butyl n-butyl OH H

H 7-dimethylamino 1409 n-butyl n-butyl OH H

H 7-dimethylamino 1410 n-butyl n-butyl OH H

H 7-dimethylamino 1411 n-butyl n-butyl OH H

H 7-dimethylamino 1412 n-butyl n-butyl OH H

H 7-dimethylamino 1413 n-butyl n-butyl OH H

H 7-dimethylamino 1414 n-butyl n-butyl OH H

H 7-dimethylamino 1415 n-butyl n-butyl OH H

H 7-dimethylamino 1416 n-butyl n-butyl OH H

H 7-dimethylamino 1417 n-butyl n-butyl OH H

H 7-dimethylamino 1418 n-butyl n-butyl OH H

H 7-dimethylamino 1419 n-butyl n-butyl OH H

H 7-dimethylamino 1420 n-butyl n-butyl OH H

H 7-dimethylamino 1421 n-butyl n-butyl OH H

H 7-dimethylamino 1422 n-butyl n-butyl OH H

H 7-dimethylamino 1423 n-butyl n-butyl OH H

H 7-dimethylamino 1424 n-butyl n-butyl OH H

H 7-dimethylamino 1425 n-butyl n-butyl OH H

H 7-dimethylamino 1426 n-butyl n-butyl OH H

H 7-dimethylamino 1427 n-butyl n-butyl OH H

H 7-dimethylamino 1428 n-butyl n-butyl OH H

H 7-dimethylamino 1429 n-butyl n-butyl OH H

H 7-dimethylamino 1430 n-butyl n-butyl OH H

H 7-dimethylamino 1431 n-butyl n-butyl OH H

H 7-dimethylamino 1432 n-butyl n-butyl OH H

H 7-dimethylamino 1433 n-butyl n-butyl OH H

H 7-dimethylamino 1434 n-butyl n-butyl OH H

H 7-dimethylamino 1435 n-butyl n-butyl OH H

H 7-dimethylamino 1436 n-butyl n-butyl OH H

H 7-dimethylamino 1437 n-butyl n-butyl OH H

H 7-dimethylamino 1438 n-butyl n-butyl OH H

H 7-dimethylamino 1439 n-butyl n-butyl OH H

H 7-dimethylamino 1440 n-butyl n-butyl OH H

H 7-dimethylamino 1441 n-butyl n-butyl OH H

H 7-dimethylamino 1442 n-butyl n-butyl OH H

H 7-dimethylamino 1443 n-butyl n-butyl OH H

H 7-dimethylamino 1444 n-butyl n-butyl OH H

H 7-dimethylamino 1445 n-butyl n-butyl OH H

H 7-dimethylamino 1446 n-butyl n-butyl OH H

H 7-methoxy; 8-methoxy 1447 n-butyl n-butyl OH H

H 7-dimethylamino 1448 n-butyl n-butyl OH H

H 7-dimethylamino 1449 n-butyl n-butyl OH H

H 7-dimethylamino 1450 n-butyl n-butyl OH H phenyl H 7-dimethylamino1451 n-butyl n-butyl OH H

H 7-dimethylamino

PEG = 3400 molecular weight polyethylene glycol polymer chain PEG = 3400molecular weight polyethylene glycol polymer chain

PEG = 3400 molecular weight polyethylene glycol polymer chain C22 H25 NO3 S C22 H25 N O3 S C22 H28 O3 S C21 H24 O3 S C22 H25 O S C22 H25 O S387.543 387.543 372.529 336.486 340.53 340.53

C22 H25 O4 S C22 H32 O3 S . C22 H25 O3 S C22 H28 O2 S C28 H41 N O3 S C22H27 I O3 S C24 H30 O3 S 388.528 745.085 356.529 471.704 438.425 430.165

C22 H25 N O4 S C22 H25 N O4 S C28 H41 N O3 S C28 H40 O4 S C24 H30 O3 S403.543 403.543 471.704 472.689 430.383

C36 H43 N O6 S C23 H30 O4 S C22 H29 O4 S C24 H32 O4 S 617.807 402.335388.528 416.382

C22 H28 O3 S C22 H28 O3 S C23 H30 O4 S C22 H28 O4 S . C22 H28 O3 S 2 C22H28 O3 S2 372.929 372.929 402.999 761.036 404.595

C22 H26 I2 O3 S C21 H24 O3 S C23 H30 O4 S C23 H30 O4 S 624.322 236.486402.335 402.335

C18 H20 O3 S C18 H20 O3 S C22 H28 O2 S C18 H20 O2 S C22 H28 O3 S 316.421316.421 336.329 300.422 372.529

[0148] In further compounds of the present invention, R⁵ and R⁶ areindependently selected from among hydrogen and ring-carbon substitutedor unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole,imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium,N-alkyl-piperazinium, N-alkylmorpholinium, or furan in which thesubstituent(s) are selected from among halo, hydroxyl, trihaloalkyl,alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammoniumsalts, a C₁ to C₄ alkylene bridge having a quaternary ammonium saltsubstituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxyand arylcarbonyloxy, (O,O)-dioxyalkylene, —[O(CH₂)_(w)]_(x)X where x is2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt,thiophene, pyricine, pyrrole, thiazole, imidazole, pyrazole, or furan.The aryl group of R⁵ or R⁶ is preferably phenyl, phenylene, or benzenetriyl, i.e., may be unsubstituted, mono-substituted, or di-substituted.Among the species which may constitute the substituents on the aryl ringof R⁵ or R⁶ are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy,trimethylammonium (preferably with an iodide or chloride counterion),methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl,(N)-hexyldimethylammonium, hexylenetrimethylammonium,tri(oxyethylene)iodide, and tetra(oxyethylene)trimethylammonium iodide,each substituted at the p-position, the m-position, or both of the arylring. Other substituents that can be present on a phenylene, benzenetriyl or other aromatic ring include 3,4-dioxymethylene (5-memberedring) and 3,4-dioxyethylene (6- membered ring). Among compounds whichhave been or can be demonstrated to have desirable ileal bile acidtransport inhibiting properties are those in which R⁵ or R⁶ is selectedfrom phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl,m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl,p-N,N-dimethylaminophenyl, m-N,N-dimethylaminophenyl, I⁻p-(CH₃)₃—N⁺-phenyl, I⁻ m-(CH₃)₃—N⁺-phenyl, I⁻m-(CH₃)₃—N⁻—CH₂CH₂—(OCH₂CH₂)₂—O-phenyl, I⁻p-(CH₃)₃—N—CH₂CH₂—(OCH₂CH₂)₂—O-phenyl, I^(—)m-(N,N-dimethylpiperazinium)-(N′)—CH₂—(OCH₂CH₂)₂—O-phenyl,3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl,3,4-difluorophenyl, I⁻p-(N,N-dimethylpiperazinium)-(N′)—CH₂—(OCH₂CH₂)₂—O-phenyl,3-fluoro-4-methoxyphenyl, 4-pyridinyl, 2-pyridinyl, 3-pyridinyl,N-methyl-4-pyridinium, I⁻ N-methyl-3-pyridinium,3,4-dioxymethylenephenyl, 3,4-dioxyethylenephenyl, andp-methoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and3-butyl-3-butyl compounds having each of the above preferred R⁵substituents in combination with the R^(x) substituents shown inTable 1. It is particularly preferred that one but not both of R⁵ and R⁶is hydrogen.

[0149] It is especially preferred that R⁴ and R⁶ be hydrogen, that R³andR⁵ not be hydrogen, and that R³ and R⁵ be oriented in the same directionrelative to the plane of the molecule, i.e., both in α- or both inβ-configuration. It is further preferred that, where R² is butyl and R¹is ethyl, then R¹ has the same orientation relative to the plane of themolecule as R³ and R⁵.

[0150] Set forth in Table 1A are lists of species of R¹/R², R⁵/R⁶ andR^(x). TABLE 1A Alternative R groups

R¹, R² R³, R⁴ R⁵ (R^(x))q ethyl HC— Ph— 7-methyl n-propyl H— p-F—Ph—7-ethyl n-butyl m-F—Ph— 7-iso-propyl n-pentyl p-CH₃O—Ph— 7-tert-butyln-hexyl 7-OH iso-propyl m-CH₃O—Ph— 7-OCH₃ iso-butyl p-(CH₃)₂N—Ph—7-O(iso-propyl) iso-pentyl m-(CH₃)₂N—Ph— 7-SCH₃ CH₂C(═O)C₂H₅ I⁻,p-(CH₃)₃—N⁺—Ph— 7-SCCH₃ CH₂CC₂H₅ I⁻, m-(CH₃)₃—N⁺—Ph— 7-SO₂CH₃CH₂CH(CH)C₂H₅ I⁻, p-(CH₃)₃—N⁺—CH₂CH₂— 7-SCH₂CH₃ CH₂O-(4-picoline)(OCH₂CH₂)₂—O—Ph— 7-NH₂ I⁻, m-(CH₃)₃—N⁺—CH₂CH₂— 7-NHCH (OCH₂CH₂)₂—O—Ph—7-NHCH₃ I⁻, p-(N,N- 7-N(CH₃)₂ dimethylpiperazine)- 7-N⁺(CH₃)₃, I⁻(N′)—CH₂—(OCH₂CH₂)₂—O— 7-NHC(═O)CH₃ Ph— 7-N(CH₂CH₃)₂ I⁻, m-(N,N-7-NMeCH₂CO₂H dimethylpiperazine)- 7-N⁺(Me)₂CH₂CO₂H, I⁻(N′)-CH₂—(OCH₂CH₂)₂—O— 7-(N)-morpholine Ph— 7-(N)-azetidine m-F,p-CH₃C—Ph— 7-(N)-N-methylazetidinium, I⁻ 3,4,dioxymethylene-Ph7-(N)-pyrrolidine m-CH₃O—, p-F—Ph— 7-(N)-N-methyl-pyrrolidinium, I⁻4-pyridine 7-(N)-N-methyl-morpholinium, I⁻ N-methyl-4-pyridinium, I⁻7-(N)-N′-methylpiperazine 3-pyridine 7-(N)-N′-dimethylpiperazinium, I⁻N-methyl-3-pyridinium, I⁻ 7-NH—CBZ 2-pyridine 7-NHC(═O)C₅H₁₁p-CH₃O₂C—Ph— 7-NHC(═O)CH₂Br thienyl-2-yl 7-NH—C(NH)NH₂ 5-Cl-thienyl-2-yl7-(2)-thiephene 3,4-difluoro m-F, P—CH₃O—Ph 8-methyl 8-ethyl8-iso-propyl 8-tert-butyl 8-OH 8-OCH₃ 8-O(iso-propyl) 8-SCH₃ 8-SOCH₃8-SO₂CH₃ 8-SCH₂CH₃ 8-NH₂ 8-NHCH 8-NHCH₃ 8-N(CH₃)₂ 8-N⁺(CH₃)₃, I⁻8-NHC(═O)CH₃ 8-N(CH₂CH₃)₂ 8-NMeCH₂CO₂H 8-N⁺(Me)₂CH₂CO₂H, I⁻8-(N)-morpholine 8-(N)-azetidine 8-(N)-N-methylazetidinium, I⁻8-(N)-N-pyrrolidine 8-(N)-N-methyl-pyrrolidinium, I⁻8-(N)-N-methyl-morpholinium, I⁻ 8-(N)-N′-methylpiperazine8-(N)-N′-dimethylpiperazinium, I⁻ 8-NH—CBZ 8-NHC(O)C₅H₁₁ 8-NHC(O)CH₂Br8-NH—C(NH)NH₂ 8-(2)-thiephene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl9-OH 9-OCH₃ 9-O(iso-propyl) 9-SCH₃ 9-SOCH₃ 9-SO₂CH₃ 9-SCH₂CH₃ 9-NH₂9-NHCH 9-NHCH₃ 9-N(CH₃)₂ 9-N⁺(CH₃)₃, I⁻ 9-NHC(═O)CH₃ 9-N(CH₂CH₃)₂9-NMeCH₂CO₂H 9-N⁺(Me)₂CH₂CO₂H, I⁻ 9-(N)-morpholine 9-(N)-azetidine9-(N)-N-methylazetidinium, I⁻ 9-(N)-N-pyrrolidine9-(N)-N-methyl-pyrrolidinium, I⁻ 9-(N)-N-methyl-morpholinium, I⁻9-(N)-N′-methylpiperazine 9-(N)-N′-dimethylpiperazinium, I⁻ 9-NH—CBZ9-NHC(O)C₅H₁₁ 9-NHC(O)CH₂Br 9-NH—C(NH)NH₂ 9-(2)-thiephene 7-OCH₃, 8-OCH₃7-SCH₃, 8-OCH₃ 7-SCH₃, 8-SCH₃ 6-OCH₃, 7-OCH₃, 8-OCH₃

[0151] Further preferred compounds of the present invention comprise acore structure having two or more pharmaceutically active benzothiepinestructures as described above, covalently bonded to the core moiety viafunctional linkages. Such active benzothiepine structures preferablycomprise:

[0152] where R¹, R², R³, R⁴, R⁶, R⁵, R⁶, R⁷, R⁸, X, q and n are asdefined above, and R⁵⁵ is either a covalent bond or arylene.

[0153] The core moiety can comprise alkane diyl, alkene diyl, alkynediyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl,alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl,polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, canoptionally have one or more carbon replaced by O, NR⁷, N⁺R⁷R⁸, S, SO,SO₂ S⁺R⁷R⁸, PR⁷, P⁺R⁷R⁸, phenylene, heterocycle, quaternary heterocycle,quaternary heteroaryl, or aryl,

[0154] wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl,alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,peptide, and polypeptide can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, arylalkyl, halogen, oxo, OR¹³, N¹³R¹⁴, SR¹³, S(O)R¹³,SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A-,P(OR¹³)OR¹⁴, S⁻R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;

[0155] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can be further substituted withone or more substituent groups selected from the group consisting ofOR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸, and

[0156] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can optionally have one or morecarbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷,P⁺R⁷R⁸A-, or phenylene.

[0157] Exemplary core moieties include:

[0158] wherein:

[0159] R²⁵ is selected from the group consisting of C and N, and

[0160] R²⁶ and R²⁷ are independently selected from the group consistingof:

[0161] wherein R²⁶, R²⁹, R³⁰ and R³¹ are independently selected fromalkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, andheteocycloalkyl,

[0162] A⁻ is a pharmaceutically acceptable anion, and k=1 to 10.

[0163] In compounds of Formula DIV, R²⁰, R²¹, R²² in Formulae DII andDIII, and R²³ in Formula DIII can be bonded at any of their 6-, 7-, 8-,or 9- positions to R¹⁹. In compounds of Formula DIVA, it is preferredthat R⁵⁵ comprises a phenylene moiety bonded at a m- or p-positionthereof to R¹⁹.

[0164] In another embodiment, a core moiety backbone, R¹⁹, as discussedherein in Formulas DII and DIII can be multiply substituted with morethan four pendant active benzothiepine units, i.e., R²⁰, R²¹, R²², andR²³ as discussed above, through multiple functional groups within thecore moiety backbone. The core moiety backbone unit, R¹⁹, can comprise asingle core moiety unit, multimers thereof, and multimeric mixtures ofthe different core moiety units discussed herein, i.e., alone or incombination. The number of individual core moiety backbone units canrange from about one to about 100, preferably about one to about 80,more preferably about one to about 50, and even more preferably aboutone to about 25. The number of points of attachment of similar ordifferent pendant active benzothiepine units within a single core moietybackbone unit can be in the range from about one to about 100,preferably about one to about 80, more preferably about one to about 50,and even more preferably about one to about 25. Such points ofattachment can include bonds to C, S, O, N, or P within any of thegroups encompassed by the definition of R¹⁹.

[0165] The more preferred benzothiepine moieties comprising R²⁰, R²¹,R²² and/or R²³ conform to the preferred structures as outlined above forformula I. The 3-carbon on each benzothiepine moiety can be achiral, andthe substituents R¹, R², R³, R⁴, R⁵ and R^(x) can be selected from thepreferred groups and combinations of substituents as discussed above.The core structures can comprise, for example, poly(oxyalkylene) oroligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- oroligo(oxypropylene).

[0166] Dosages, Formulations, and Routes of Administration

[0167] The ileal bile acid transport inhibitor compounds of the presentinvention can be administered for the prophylaxis and treatment ofhyperlipidemic diseases or conditions by any means, preferably oral,that produce contact of these compounds with their site of action in thebody, for example in the ileum of a mammal, e.g., a human.

[0168] For the prophylaxis or treatment of the conditions referred toabove, the compounds of the present invention can be used as thecompound per se.

[0169] Pharmaceutically acceptable salts are particularly suitable formedical applications because of their greater aqueous solubilityrelative to the parent compound. Such salts must clearly have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the present inventionwhen possible include those derived from inorganic acids, such ashydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic,and sulfuric acids, and organic acids such as acetic, benzenesulfonic,benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isothionic, lactic, lactobionic, maleic, malic, methanesulfonic,succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Thechloride salt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts such as sodium and potassium salts, and alkaline earth saltssuch as magnesium and calcium salts.

[0170] The anions of the definition of A⁻ in the present invention are,of course, also required to be pharmaceutically acceptable and are alsoselected from the above list.

[0171] The compounds of the present invention can be presented with anacceptable carrier in the form of a pharmaceutical composition. Thecarrier must, of course, be acceptable in the sense of being compatiblewith the other ingredients of the composition and must not bedeleterious to the recipient. The carrier can be a solid or a liquid, orboth, and is preferably formulated with the compound as a unit-dosecomposition, for example, a tablet, which can contain from 0.05% to 95%by weight of the active compound. Other pharmacologically activesubstances can also be present, including other compounds of the presentinvention. The pharmaceutical compositions of the invention can beprepared by any of the well known techniques of pharmacy, consistingessentially of admixing the components.

[0172] These compounds can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic compounds or as a combination of therapeuticcompounds.

[0173] The amount of compound which is required to achieve the desiredbiological effect will, of course, depend on a number of factors such asthe specific compound chosen, the use for which it is intended, the modeof administration, and the clinical condition of the recipient.

[0174] In general, a daily dose can be in the range of from about 0.3 toabout 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kgbodyweight/day. This total daily dose can be administered to the patientin a single dose, or in proportionate multiple subdoses. Subdoses can beadministered 2 to 6 times per day. Doses can be in sustained releaseform effective to obtain desired results.

[0175] Orally administrable unit dose formulations, such as tablets orcapsules, can contain, for example, from about 0.1 to about 100 mg ofbenzothiepine compound, preferably about 1 to about 75 mg of compound,more preferably from about 10 to about 50 mg of compound. In the case ofpharmaceutically acceptable salts, the weights indicated above refer tothe weight of the benzothiepine ion derived from the salt.

[0176] Oral delivery of an ileal bile acid transport inhibitor of thepresent invention can include formulations, as are well known in theart, to provide prolonged or sustained delivery of the drug to thegastrointestinal tract by any number of mechanisms. These include, butare not limited to, pH sensitive release from the dosage form based onthe changing pH of the small intestine, slow erosion of a tablet orcapsule, retention in the stomach based on the physical properties ofthe formulation, bioadhesion of the dosage form to the mucosal lining ofthe intestinal tract, or enzymatic release of the active drug from thedosage form. The intended effect is to extend the time period over whichthe active drug molecule is delivered to the site of action (the ileum)by manipulation of the dosage form. Thus, enteric-coated andenteric-coated controlled release formulations are within the scope ofthe present invention. Suitable enteric coatings include celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methacrylic acid methyl ester.

[0177] When administered intravenously, the dose can, or example, be inthe range of from about 0.1 mg/kg body weight to about 1.0 mg/kg bodyweight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kgbody weight, more preferably from about 0.4 mg/kg body weight to about0.6 mg/kg body weight. This dose can be conveniently administered as aninfusion of from about 10 ng/kg body weight to about 100 ng/kg bodyweight per minute. Infusion fluids suitable for this purpose cancontain, for example, from about 0.1 ng to about 10 mg, preferably fromabout 1 ng to about 10 mg per milliliter. Unit doses can contain, forexample, from about 1 mg to about 10 g of the compound of the presentinvention. Thus, ampoules for injection can contain, for example, fromabout 1 mg to about 100 mg.

[0178] Pharmaceutical compositions according to the present inventioninclude those suitable for oral, rectal, topical, buccal (e.g.,sublingual), and parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) administration, although the most suitableroute in any given case will depend on the nature and severity of thecondition being treated and on the nature of the particular compoundwhich is being used. In most cases, the preferred route ofadministration is oral.

[0179] Pharmaceutical compositions suitable for oral administration canbe presented in discrete units, such as capsules, cachets, lozenges, ortablets, each containing a predetermined amount of at least one compoundof the present invention; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil emulsion. As indicated, such compositions can be preparedby any suitable method of pharmacy which includes the step of bringinginto association the active compound(s) and the carrier (which canconstitute one or more accessory ingredients). In general, thecompositions are prepared by uniformly and intimately admixing theactive compound with a liquid or finely divided solid carrier, or both,and then, if necessary, shaping the product. For example, a tablet canbe prepared by compressing or molding a powder or granules of thecompound, optionally with one or more assessory ingredients. Compressedtablets can be prepared by compressing, in a suitable machine, thecompound in a free-flowing form, such as a powder or granules optionallymixed with a binder, lubricant, inert diluent and/or surfaceactive/dispersing agent(s). Molded tablets can be made by molding, in asuitable machine, the powdered compound moistened with an inert liquiddiluent.

[0180] Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

[0181] Pharmaceutical compositions suitable for parenteraladministration conveniently comprise sterile aqueous preparations of acompound of the present invention. These preparations are preferablyadministered intravenously, although administration can also be effectedby means of subcutaneous, intramuscular, or intradermal injection. Suchpreparations can conveniently be prepared by admixing the compound withwater and rendering the resulting solution sterile and isotonic with theblood. Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of a compound disclosed herein.

[0182] Pharmaceutical compositions suitable for rectal administrationare preferably presented as unit-dose suppositories. These can beprepared by admixing a compound of the present invention with one ormore conventional solid carriers, for example, cocoa butter, and thenshaping the resulting mixture.

[0183] Pharmaceutical compositions suitable for topical application tothe skin preferably take the form of an ointment, cream, lotion, paste,gel, spray, aerosol, or oil. Carriers which can be used includevaseline, lanoline, polyethylene glycols, alcohols, and combinations oftwo or more thereof. The active compound is generally present at aconcentration of from 0.1 to 15% w/w of the composition, for example,from 0.5 to 2%.

[0184] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal administration can be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain a compound of the present invention in an optionallybuffered, aqueous solution, dissolved and/or dispersed in an adhesive,or dispersed in a polymer. A suitable concentration of the activecompound is about 1% to 35%, preferably about 3% to 15%. As oneparticular possibility, the compound can be delivered from the patch byelectrotransport or iontophoresis, for example, as described inPharmaceutical Research, 3(6), 318 (1986).

[0185] In any case, the amount of active ingredient that can be combinedwith carrier materials to produce a single dosage form to beadministered will vary depending upon the host treated and theparticular mode of administration.

[0186] The solid dosage forms for oral administration includingcapsules, tablets, pills, powders, and granules noted above comprise oneor more compounds of the present invention admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms mayalso comprise, as in normal practice, additional substances other thaninert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets, and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings.

[0187] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0188] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or setting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0189] Pharmaceutically acceptable carriers encompass all the foregoingand the like.

[0190] In combination therapy, administration of the ileal bile acidtransport inhibitor and HMG Co-A reductase inhibitor may take placesequentially in separate formulations, or may be accomplished bysimultaneous administration in a single formulation or separateformulations. Administration may be accomplished by oral route, or byintravenous, intramuscular, or subcutaneous injections. The formulationmay be in the form of a bolus, or in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more pharmaceutically-acceptable carriers or diluents, or a bindersuch as gelatin or hydroxypropylmethyl cellulose, together with one ormore of a lubricant, preservative, surface active or dispersing agent.

[0191] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension, or liquid.Capsules, tablets, etc., can be prepared by conventional methods wellknown in the art. The pharmaceutical composition is preferably made inthe form of a dosage unit containing a particular amount of the activeingredient or ingredients. Examples of dosage units are tablets orcapsules. These may with advantage contain one or more ileal bile acidtransport inhibitors in an amount described above. In the case of HMGCo-A reductase inhibitors, the dose range may be from about 0.01 mg toabout 500 mg or any other dose, dependent upon the specific inhibitor,as is known in the art.

[0192] The active ingredients may also be administered by injection as acomposition wherein, for example, saline, dextrose, or water may be usedas a suitable carrier. A suitable daily dose of each active inhibitor isone that achieves the same blood serum level as produced by oraladministration as described above.

[0193] The active inhibitors may further be administered by any dualcombination of oral/oral, oral/parenteral or parenteral/parenteralroute.

[0194] Pharmaceutical compositions for use in the treatment methods ofthe present invention may be administered in oral form or by intravenousadministration. Oral administration of the combination therapy ispreferred. Dosing for oral administration may be with a regimen callingfor single daily dose, or for a single dose every other day, or formultiple, spaced doses throughout the day. The inhibitors which make upthe combination therapy may be admiminstered simultaneously, either in acombined dosage form or in separate dosage forms intended forsubstantially simultaneous oral administration. The inhibitors whichmake up the combination therapy may also be administered sequentially,with either inhibitor being administered by a regimen calling fortwo-step ingestion. Thus, a regimen may call for sequentialadministration of the inhibitors with spaced-apart ingestion of theseparate, active agents. The time period between the multiple ingestionsteps may range from a few minutes to several hours, depending upon theproperties of each inhibitor such as potency, solubility,bioavailability, plasma half-life and kinetic profile of the inhibitor,as well as depending upon the age and condition of the patient. Theinhibitors of the combined therapy whether administered simultaneously,substantially simultaneously, or sequentially, may involve a regimencalling for administration of one inhibitor by oral route and the otherinhibitor by intravenous route. Whether the inhibitors of the combinedtherapy are administered by oral or intravenous route, separately ortogether, each such inhibitor will be contained in a suitablepharmaceutical formulation of pharmaceutically-acceptable excipients,diluents or other formulations components. Examples of suitablepharmaceutically-acceptable formulations containing the inhibitors fororal administration are given above.

[0195] Treatment Regimen

[0196] The dosage regimen to prevent, give relief from, or ameliorate adisease condition having hyperlipemia as an element of the disease,e.g., atherosclerosis, or to protect against or treat further highcholesterol plasma or blood levels with the compounds and/orcompositions of the present invention is selected in accordance with avariety of factors. These include the type, age, weight, sex, diet, andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetics and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized, andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforedeviate from the preferred dosage regimen set forth above.

[0197] Initial treatment of a patient suffering from a hyperlipidemiccondition can begin with the dosages indicated above. Treatment shouldgenerally be continued as necessary over a period of several weeks toseveral months or years until the hyperlipidemic disease condition hasbeen controlled or eliminated. Patients undergoing treatment with thecompounds or compositions disclosed herein can be routinely monitoredby, for example, measuring serum LDL and total cholesterol levels by anyof the methods well known in the art, to determine the effectiveness ofthe combination therapy. Continuous analysis of such data permitsmodification of the treatment regimen during therapy so that optimaleffective amounts of each type of inhibitor are administered at anypoint in time, and so that the duration of treatment can be determinedas well. In this way, the treatment regimen/dosing schedule can berationally modified over the course of therapy so that the lowest amountof ileal bile acid transport inhibitor and HMG Co-A reductase inhibitorwhich together exhibit satisfactory effectiveness is administered, andso that administration is continued only so long as is necessary tosuccessfully treat the hyperlipidemic condition.

[0198] A potential advantage of the combination therapy disclosed hereinmay be reduction of the amount of ileal bile acid transport inhibitor,HMG Co-A reductase inhibitor, or both, effective in treatinghyperlipidemic conditions such as atherosclerosis andhypercholesterolemia.

[0199] The following non-limiting examples serve to illustrate variousaspects of the present invention.

EXAMPLES OF SYNTHETIC PROCEDURES

[0200] Preparation 1

[0201] 2-Ethyl-2-(mesyloxymethyl)hexanal (1)

[0202] To a cold (10° C.) solution of 12.6 g (0.11 mole) ofmethanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine wasadded dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, preparedaccording to the procedure described in Chem. Ber. 98, 728-734 (1965),while maintaining the reaction temperature below 30° C. The reactionmixture was stirred at room temperature for 18 h, quenched with diluteHCl and extracted with methlyene chloride. The methylene chlorideextract was dried over MgSO₄ and concentrated in vacuo to give 24.4 g ofbrown oil.

[0203] Preparation 2

[0204] 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

[0205] A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, preparedaccording to the procedure described in WO 93/16055, 24.4 g (0.1 mole)of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) oftriethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for24 h. The reaction mixture was poured into 3N HCl and extracted with 300mL of methylene chloride. The methylene chloride layer was washed with300 mL of 10% NaOH, dried over MgSO₄ and concentrated in vacuo to remove2-methoxyethyl ether. The residue was purified by HPLC (10%EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.

Example 1

[0206] 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3),cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one (4a) andtrans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one (4b)

[0207] A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole)of TiCl₃ and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) washeld at reflux or 2 h. The reaction mixture was cooled to 5° C. To thereaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of2 in 30 mL of DME in 40 min. The reaction mixture was stirred at roomtemperature for 16 h and then was held at relux for 2 h and cooledbefore being poured into brine. The organic was extract into methylenechloride. The methylene chloride extract was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by HPLC (hexane) to give1.7 g (43%) of 3 as an oil in the first fraction. The second fractionwas discarded and the third fraction was further purified by HPLC(hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g(3%) of 4b in the later fraction.

Example 2

[0208]cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one-1,1-dioxide(5a) andtrans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one-1,1-dioxide(5b)

[0209] To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL ofmethylene chloride was added 0.59 g (1.75 mmole) of a mixture of 4a and4b in 10 mL of methylene chloride. The reaction mixture was stirred for20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and thereaction mixture was stirred for an additional 3 h then was trituratedwith 50 mL of 10% NaOH. The insoluble solid was filtered. The methylenechloride layer of the filtrate was washed with brine, dried over MgSO₄,and concentrated in vacuo. The residual syrup was purified by HPLC (5%EtOAc-hexane) to give 0.2 g (30%) of 5a as an oil in the first fractionand 0.17 g (26%) of 5b as an oil in the second fraction.

Example 3

[0210]

[0211] (3a,4a,5b)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6a), (3a,4b,5a)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(6b), (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6c), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6d)

[0212] A. Reduction of 5a and 5b with Sodium Borohydride

[0213] To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanolwas added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixturewas stirred at room temperature for 18 h and concentrated in vacuo toremove ethanol. The residue was triturated with water and extracted withmethylene chloride. The methylene chloride extract was dried over MgSO₄and concentrated in vacuo to give 0.2 g of syrup. In a separateexperiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydridein 10 mL of ethanol and was worked up as described above to give 0.5 gof syrup which was identical to the 0.2 g of syrup obtained above. Thesetwo materials were combined and purified by HPLC using 10% EtOAc-hexaneas eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. Thesecond fraction was 0.2 g (30%) of 6b also as a syrup. The column wasthen eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in thethird fraction as a solid. Recrystallization from hexane gave a solid,mp 179-181° C. Finally, the column was eluted with 30% EtOAc-hexane togive 0.08 g (12%) of 6d in the fourth fraction as a solid.

[0214] Recrystallization from hexane gave a solid, mp 160-161° C.

[0215] B. Conversion of 6a to 6c and 6d with NaOH and PTC

[0216] To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH₂Cl₂, wasadded 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h atroom temperature and was added one drop of Aliquat-336(methyltricaprylylammonium chloride) phase transfer catalyst (PTC). Themixture was stirred for 0.5 h at room temperature before being treatedwith 25 mL of ice-crystals then was extracted with CH₂Cl₂ (3×10 ml),dried over MgSO₄ and concentrated in vacuo to recover 0.17 g of acolorless film. The components of this mixture were separated using anHPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction,30.9 mg (11%) of 6c in the second fraction and 90.0 mg (31%) of 6d inthe third fraction.

[0217] Oxidation of 6a to 5b

[0218] To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH₂Cl₂ wasadded 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reactionmixture was stirred for 2 h then was treated with additional 0.23 g ofpyridinium chlorochromate and stirred overnight. The dark reactionmixture was poured into a ceramic filterfrit containing silica gel andwas eluted with CH₂Cl₂. The filtrate was concentrated in vacuo torecover 167 mg (87%) of 5b as a colorless oil.

Example 4

[0219] 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-dioxide (7)

[0220] To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH₂Cl₂ wasadded 10 g (31.9 mmole) of 50-60% MCPBA (m-chloroperoxybenzoic acid)portionwise causing a mild reflux and formation of a white solid. Thereaction mixture was allowed to stir overnight under N₂ and wastriturated with 25 mL of water followed by 50 mL of 10% NaOH solution.The organic was extracted into CH₂Cl₂ (4×20 mL). The CH₂Cl₂ extract wasdried over MgSO₄ and evaporated to dryness to recover 4.9 g (87%) of anopaque viscous oil.

Example 5

[0221] (1aa,2b,8ba)2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(8a) (1aa,2a,8ba)2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8b)

[0222] To 1.3 g (4.03 mole) of 3 in 25 mL of CHCl₃ was added portionwise5 g (14.1 mmole) of 50-60% MCPBA causing a mild exotherm. The reactionmixture was stirred under N₂ overnight and was then held at reflux for 3h. The insoluble white slurry was filtered. The filtrate was extractedwith 10% potassium carbonate (3×50 mL), once with brine, dried overMgSO₄, and concentrated in vacuo to give 1.37 g of a light yellow oil.Purification by HPLC gave 0.65 g of crystalline product. This product isa mixture of two isomers. Trituration of this crystalline product inhexane recovered 141.7 mg (10%) of a white crystalline product. Thisisomer was characterized by NMR and mass spectra to be the (1aa,2b,8ba)isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mgof white film which is a mixture of 30% 8a and 70% 8b by ¹H NMR.

Example 6

[0223]

[0224]cis-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(9a),trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(9b), and3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(10)

[0225] A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b wasdissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H₂for 5 h and filtered. The filtrate was evaporated to dryness in vacuo torecover 0.117 g of a colorless oil. This material was purified by HPLCeluting with EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. Thesecond fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. Thethird fraction was 8.8 mg (6%) of 6a. The fourth fraction was 25.5 mg(18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and aproduct believed to be3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxidebased on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixtureof 6d and one of the isomers of 10, 10a.

Example 7

[0226] In another experiment, a product (3.7 g) from epoxidation of 3with excess MCPBA in refluxing CHCl₃ under air was hydrogenated in 100mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. Theproduct was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g(2%) of one isomer of 10, 10a and 0.03 g (1%) of another isomer of 10,10b.

Example 8

[0227]

[0228] 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11)

[0229] To an ice bath cooled solution of 9.76 g (0.116 mole) of2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) oftriethylamine. The reaction mixture was stirred at room temperature for3 days, diluted with ether, and was washed successively with dilute HCl,brine, and 1 M potassium carbonate. The ether layer was dried over MgSO₄and concentrated in vacuo. The residue was purified by HPLC (10%EtoAc-hexane) to give 22 g (64%) of 11 in the second fraction. Anattempt to further purifiy this material by kugelrohr distillation at0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained startingmaterial indicating a reversed reaction during distillation. Thismaterial was dissolved in ether (100 mL) and was washed with 50 mL of 1M potassium, carbonate three times to give 6.0 g of a syrup which waspurified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 9

[0230]

[0231] 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12)

[0232] To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DMEwas added 7.5 g (0.048 mole) of TiCl₃. The reaction mixture was held atreflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was addeddropwise in 1 h. The reaction mixture was held at reflux for 18 h,cooled and poured into water. The organic was extracted into ether. Theether layer was washed with brine and filtered through Celite. Thefiltrate was dried over MgSO₄ and concentrated. The residual oil (2.5 g)was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the secondfraction.

Example 10

[0233]

[0234] (1aa,2a,8ba)2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino-[4,5-b]oxirene-4,4-dioxide(13)

[0235] To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHCl₃ wasadded 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothemand formation of a white solid. The mixture was stirred at roomtemperature overnight diluted with 100 ml methylene chloride and washedsuccessively with 10% K₂CO₃ (4×50 ml), water (twice with 25 ml) andbrine. The organic layer was then dried over MgSO₄ and evaporated todryness to recover 1.47 g of an off white solid. ¹H NMR indicated thatonly one isomer is present. This solid was slurried in 200 ml of warmEt₂O and filtered to give 0.82 g (46%) of 13 as a white solid, mp185-186.5° C.

Example 11

[0236](3a,4b,5a)-3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(14a), (3a,4b,5b)3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(14b), andcis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (15)

[0237] A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h.The crude reaction slurry was filtered and the filtrate was stirred with150 ml of a saturated NaHCO₃ solution followed by 89 g of NaHCO₃ powderportionwise to neutralize the rest of acetic acid. The mixture wasextracted with methylene chloride (4×25 ml), then the organic layer wasdried over MgSO₄ and concentrated in vacuo to give 0.44 g (87%) of avoluminous white solid which was purified by HPLC (EtOAc-Hexane) to give26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as asolid, mp 142-143.5° C., in the second fraction, and 35 mg (7%) ofimpure 14b in the third fraction.

Example 12

[0238] 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16)

[0239] A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g ofmercaptobenzyl alcohol and 0.72 g of triethylamine was added to thereaction mixture and the mixture was held at reflux for additional 16 h.The reaction mixture was cooled and poured into 6N HCl and extractedwith methylene chloride. The methylene chloride extract was washed twicewith 10% NaOH, dried over MgSO₄ and concentrated in vacuo to give 9.6 gof residue. Purification by EPLC (20% EtOAc-hexane) gave 3.7 g (41%) of16 as an oil.

Example 13

[0240]

[0241] 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17)

[0242] A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridiniumchlorochromate, 2 g of Celite and 30 mL of methylene chloride wasstirred for 18 h and filtered through a bed of silica gel. The silicagel was eluted with methylene chloride. The combined methylene chlorideeluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of anoil.

Example 14

[0243]

[0244] 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18)

[0245] A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole)of TiCl₃, and 50 mL of DME was held at reflux for 2 h and cooled to roomtemperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mLof DME in 10 min. The reaction mixture was stirred at room temperaturefor 2 h and held at reflux for 1 h then was let standing at roomtemperature over weekend. The reaction mixture was poured into diluteHCl and was stirred with methylene chloride. The methylenechloride-water mixture was filtered through Celite. The methylenechloride layer was washed with brine, dried to over MgSO₄, andconcentrated in vacuo to give 3.0 g of a residue. Purification by HPLCgave 0.41 g (20%) of 18 as an oil in the early fraction.

Example 15

[0246] (1aa,2a,8ba)2-Butyl-2-ethyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(19a) and (1aa,2b,8ba)2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(19b)

[0247] To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL ofmethylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. Thereaction mixture was stirred for 2 h and concentrated in vacuo. Theresidue was dissolved in 30 mL of CHCl₃ and was held at reflux for 18 hunder N₂. The reaction mixture was stirred with 100 mL of 10% NaOH and 5g of sodium sulfite. The methylene chloride layer was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified byHPLC (20% EtOAc-hexane) to give a third fraction which was furtherpurified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the firstfraction.

[0248] Recrystallization from hexane gave 0.08 g (17%) of 19a, mp89.5-105.5° C. The mother liquor from the first fraction was combinedwith the second fraction and was further purified by HPLC to giveadditional 19a in the first fraction and 60 mg of 19b in the secondfraction. Crystallization from hexane gave 56 mg of a white solid.

Example 16

[0249]3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(20)

[0250] This product was isolated along with 6b from hydrogenation of amixture of 8a and 8b.

Example 17

[0251]3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(21)

[0252] A mixture of 25 mg (0.085 mole) of 19b, 0.27 g (2.7 mmole) ofthiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMFwas stirred at room temperature under N₂ for 19 h. The reaction mixturewas poured into water and extracted with methylene chloride. Themethylene chloride layer was washed successively with 10% NaOH andbrine, dried over MgSO₄, and concentrated in vacuo to give 0.19 g ofsemisolid which contain substantial amounts of diphenyl disulfide. Thismaterial was purified by HPLC (5% EtOAc-hexane) to remove diphenyldisulfide in the first fraction. The column was then eluted with 20%EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a secondfraction and 11 mg of a third fraction which were three differentisomers of 21, i.e. 21a, 21b, and 21c, respectively, by ¹H NMR and massspectra.

Example 18

[0253] Alternative Synthesis of 6c and 6d

[0254] A. Preparation from2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

[0255] Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2-ethylhexanal (44)

[0256] To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml ofmethylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBAportionwise. The reaction mixture was stirred at room temperature for 64h then was stirred with 200 ml of 1 M potassium carbonate and filteredthrough Celite. The methylene chloride layer was washed twice with 300ml of 1 M potassium carbonate, once with 10% sodium hydroxide and oncewith brine. The insoluble solid formed during washing was removed byfiltration through Celite. The methylene chloride solution was dried andconcentrated in vacuo to give 9.2 g (95%) of semisolid. A portion (2.6g) of this solid was purified by HPLC (10% ethyl acetate-hexane) to give1.9 g of crystals, mp 135-136° C.

[0257] Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

[0258] A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylenechloride was divided in two portions and charged to two Fisher-Porterbottles. To each bottle was charged 125 ml of methanol and 5 g of 10%Pd/C. The bottles were pressurized with 70 psi of hydrogen and thereaction mixture was stirred at room temperature for 7 h before beingcharged with an additional 5 g of 10% Pd/C. The reaction mixture wasagain hydrogenated with 70 psi of hydrogen for 7 h. This procedure wasrepeated one more time but only 1 g of Pd/C was charged to the reactionmixture. The combined reaction mixture was filtered and concentrated invacuo to give 46.8 g of 45 as brown oil.

[0259] Step 3. (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6c), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6d)

[0260] To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrousTHF cooled to 2° C. with an ice bath was added 9.7 g (73.4 mmole) of 95%potassium t-butoxide. The reaction mixture was stirred for 20 min,quenched with 300 ml of 10% HCl and extracted with methylene chloride.The methylene chloride layer was dried over magnesium sulfate andconcentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC(ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the firstfraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6din the third fraction.

[0261] B. Preparation from 2-hydroxydiphenylmethane

[0262] Step 1. 2-mercaptodiphenylmethane (46)

[0263] To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodiumhydride oil dispersion. The sodium hydride was washed twice with 50 mlof hexane. To the reaction flask was charged 100 ml of DMF. To thismixture was added a solution of 55.2 g (0.3 mol) of2-hydroxydiphenylmethane in 200 ml of DLS in 1 h while temperature wasmaintained below 30° C. by an ice-water bath. After complete addition ofthe reagent, the mixture was stirred at room temperature for 30 min thencooled with an ice bath. To the reaction mixture was added 49.4 g (0.4mole) of dimethyl thiocarbamoyl chloride at once. The ice bath wasremoved and the reaction mixture was stirred at room temperature for 18h before being poured into 300 ml of water. The organic was extractedinto 500 ml of toluene. The toluene layer was washed successively with10% sodium hydroxide and brine and was concentrated in vacuo to give78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenylthiocarbamate. This oil was heated at 280-300° C. in a kugelrohr potunder house vacuum for 30 min. The residue was kugelrohr distilled at 1torr (180-280° C.) The distillate (56.3 g) was crystallized frommethanol to give 37.3 g (46%) of the rearranged product dimethylS-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g(0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 mlof methanol was stirred overnight then was concentrated in vacuo. Theresidue was diluted with 200 ml of water and extracted with ether. Theaqueous layer was made acidic with concentrate HCl, The oily suspensionwas extracted into ether. The ether extract was dried over magnesiumsulfate and concentrated in vacuo. The residue was crystallized fromhexane to give 37.1 g (88%) of 2-mercaptodiphenylmethane as a yellowsolid.

[0264] Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47)

[0265] A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g(0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) oftriethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6hr and concentrated in vacuo. The residue was triturated with 500 ml ofwater and 30 ml of concentrate HCl. The organic was extracted into 400ml of ether. The ether layer was washed successively with brine, 10%sodium hydroxide and brine and was dried over magnesium sulfate andconcentrated in vacuo. The residue (98.3 g) was purified by HPLC with2-5% ethyl acetate-hexane as eluent to give2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.

[0266] Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

[0267] To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2in 1 liter of methylene chloride cooled to 10° C. was added 132 g of50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. Anadditional 13 g of 50-60% MCPBA was added to the reaction mixture. Thereaction mixture was stirred for 2 h and filtered through Celite. Themethylene chloride solution was washed twice with 1 liter of 1 Mpotassium carbonate then with 1 liter of brine. The methylene chloridelayer was dried over magnesium sulfate and concentrated to 76 g of2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.

[0268] Step 4. (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6c), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6d)

[0269] Reaction of 45 with potassium t-butoxide according to theprocedure in step 3 of procedure A gave pure 6c and 6d after HPLC.

Example 19

[0270]

[0271] (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(25) and (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(26) Step 1. Preparation of 2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22)

[0272] 2-Hydroxy-4-methoxybenzophenone was converted to the dimethylO-2-benzoyphenyl thiocarbamate by methods previously described inexample 18. The product can be isolated by recrystallization fromethanol. Using this improved isolation procedure no chromatography wasneeded. The thermal rearrangement was performed by reacting thethiocarbamate (5 g) in diphenyl ether at 260° C. as previouslydescribed. The improved isolation procedure which avoided achromatography step was described below.

[0273] The crude pyrolysis product was then heated at 65° C. in 100 mlof methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h.After removing THF and methanol by rotary evaporation the solution wasextracted with 5% NaOH and ether. The base layer was acidified andextracted with ether to obtain a 2.9 g of crude thiophenol product. Theproduct was further purified by titrating the desired mercaptan intobase with limited KOH. After acidification and extraction with etherpure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.

[0274] 2-mercapto-4-methoxybenzophenone can readily be converted to the2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22) byreaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previouslydescribed.

[0275] Step 2.2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (23)

[0276] Substrate 22 was readily oxidized to2-((2-benzoyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (23) asdescribed in example 18.

[0277] Step 3.2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (24)

[0278] Sulfone 23 was then reduced to2-((2-benzyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (24) asdescribed in example 18.

[0279] Step 4. (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(25) and (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(26)

[0280] A 3-neck flask equipped with a powder addition funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) ofsulfone 24 in 100 ml dry THF. The reaction was cooled to −1.6° C.internal temperature by means of ice/salt bath. Slowly add 5.61 g (0.05mole) of potassium t-butoxide by means of the powder addition funnel.The resulting light yellow solution was maintained at −1.6° C. After 30min reaction 400 ml of cold ether was added and this solution wasextracted with cold 10% HCl. The acid layer was extracted with 300 ml ofmethylene chloride. The organic layers were combined and dried overmagnesium sulfate and after filtration stripped to dryness to obtain19.9 g of product. ¹H NMR and glpc indicated a 96% conversion to a 50/50mixture of 25 and 26. The only other observable compound was 4% startingsulfone 24.

[0281] The product was then dissolved in 250 ml of 90/10 hexane/ethylacetate by warming to 50° C. The solution was allowed to cool to roomtemperature and in this way pure 26 can be isolated. The crystallizationcan be enhanced by addition of a seed crystal of 26. After 2crystallizations the mother liquor which was now 85.4% 25 and has a dryweight of 8.7 g. This material was dissolved in 100 ml of 90/10hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25can be isolated by seeding this solution with a seed crystal of 25 afterstoring it overnight at 0 C.

Example 20

[0282]

[0283] (3a,4a,5a)3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(27)

[0284] In a 25 ml round bottomed flask, 1 g of 26(2.5 mmoles) and 10 mlmethylene chloride were cooled to −78° C. with stirring. Next 0.7 ml ofboron tribromide (7.5 mmole) was added via syringe. The reaction wasallowed to slowly warm to room temperature and stirred for 6 h. Thereaction was then diluted with 50 ml methylene chloride and washed withsaturated NaCl and then water. The organic layer was dried overmagnesium sulfate. The product (0.88 g) 27 was characterized by NMR andmass spectra.

Example 21

[0285] General Alkylation of phenol 27

[0286] A 25 ml flask was charged with 0.15 g of 27 (0.38 mmole), 5 mlanhydrous DMF, 54 mg of potassium carbonate (0.38 mmole) and 140 mgethyl iodide (0.9 mmole). The reaction was stirred at room temperatureovernight. The reaction was diluted with 50 ml ethyl ether and washedwith water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. Afterstripping off the solvent the ethoxylated product 28 was obtained inhigh yield. The product was characterized by NMR and mass spectra. Thissame procedure was used to prepare products listed in table 1 from thecorresponding iodides or bromides. For higher boiling alkyl iodides andbromides only one equivalent of the alkyl halide was used.

TABLE 1 Compound No. R 27 H 26 Me 28 Et 29 hexyl 30 Ac 31(CH2)6-N-pthalimide

Example 22

[0287] (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(37) and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(38)

[0288] Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32)

[0289] Procedure adapted from reference:Synthesis -Stuttgart 9 770-772(1986) Olah G. Et al

[0290] Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole)of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and thesolution was cooled to ice/water temperature. By means of an additionalfunnel, 150 g (0.172 mole) of trifluoromethane sulfonic acid in 345 mlmethylene chloride was added slowly. Next 30 g of trimethylsilane (0.172mole) in 345 ml methylene chloride was added dropwise to the chilledsolution. Both addition steps (trifluoromethane sulfonic acid andtriethylsilane) were repeated. After the additions were completed thereaction was allowed to slowly warm up to room temperature and stirredfor 12 h under nitrogen. The reaction mixture was then poured into achilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gasevolution occurred. Poured into a 4 liter separatory funnel andseparated layers. The methylene chloride layer was isolated and combinedwith two 500 ml methylene chloride extractions of the aqueous layer. Themethylene chloride solution was dried over magnesium sulfate andconcentrated in vacuo. The residue was recrystallized from hexane togive 39 g product. Structure 32 was confirmed by mass spectra and protonand carbon NMR.

[0291] Step 2. Preparation of2-((2-benzyl-4-nitrophenylthio)methyl)-2-ethylhexanal (33)

[0292] The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole)from above was placed in a 2 liter 2 neck flask with water condenser.Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was addedand the solution was stirred at 75° C. for 12 h. The reaction was cooledto room temperature and then 51.7 g of mesylate IV was added in 90 mlDMSO. The reaction mixture was heated to 80° C. under nitrogen. After 12h monitored by TLC and added more mysylate if necessary. Continued thereaction until the reaction was completed. Next the reaction mixture wasslowly poured into a 1900 ml of 5% acetic aqueous solution withstirring, extracted with 4×700 ml of ether, and dried over MgSO4. Afterremoval of ether, 82.7 g of product was isolated. The material can befurther purified by silica gel chromatography using 95% hexane and 5%ethyl acetate. If pure mysylate was used in this step there was no needfor further purification. The product 33 was characterized by massspectra and NMR.

[0293] Step 3. Oxidation of the nitro product 33 to the sulfone2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2-ethylhexanal (34)

[0294] The procedure used to oxidize the sulfide 33 to the sulfone 34has been previously described.

[0295] Step 4. Reduction of 34 to2-((2-benzyl-4-hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (35)

[0296] A 15 g sample of 34 was dissolved in 230 ml of ethanol and placedin a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt. % Pd/C wasadded and hydrogen gas was bubbled through the solution at roomtemperature until the nitro substrate 34 was consumed. The reactioncould be readily monitored by silica gel TLC using 80/20 hexane/EtOAc.Product 35 was isolated by filtering off the Pd/C and then stripping offthe EtOH solvent. The product was characterized by NMR and mass spectra.

[0297] Step 5. Preparation of the2-((2-benzyl-4-N,O-di-(t-butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal(36).

[0298] A 13.35 g sample of 35 (0.0344 mole) in 40 ml or dry THF wasstirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60° C. overnight.Striped off THF and redissolved in methylene chloride. Extracted with 1%HCl; and then 5% sodium bicarbonate.

[0299] The product was further purified by column chromatography using90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. Theproduct 36 was obtained (4.12 g) which appeared to be mainly thedi-(t-butoxycarbonyl) derivatives by proton NMR.

[0300] Step 6. (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(37) and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(38)

[0301] A 250 ml 3-neck round bottomed flask was charged with 4 g of 36(6.8 mmoles), and 100 ml of anhydrous THF and cooled to −78° C. under anitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide (20.4mmoles) with stirring and maintaining a −78° C. reaction temperature.After 1 h at −78° C. the addition of base was completed and thetemperature was brought to −10° C. by means of a ice/salt bath. After 3h at −10° C., only trace 36 remained by TLC. Next add 35 ml of deionizedwater to the reaction mixture at −10° C. and stirred for 5 min. Stripedoff most of the THF and added to separatory funnel and extracted withether until all of the organic was removed from the water phase. Thecombined ether phases were washed with saturated NaCl and then driedover sodium sulfate. The only products by TLC and NMR were the two BOCprotected isomers of 37 and 38. The isomers were separated by silica gelchromatography using 85% hexane and 15% ethyl acetate; BOC-37 (0.71 g)and BOC-38 (0.78 g).

[0302] Next the BOC protecting group was removed by reacting 0.87 g ofBOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles) in dioxane for30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to thereaction mixture and 16.5 ml ether and stirred until clear. Aftertransferring to a separatory funnel extracted with ether and water andthen dried the ether layer with sodium sulfate. After removing theether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in asimilar procedure.

Example 23

[0303]

[0304] (3a,4a,5a)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(40) ad (3a,4b,5b)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(41)

[0305] Step 1.2-((2-Benzyl-4-(n-hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39)

[0306] In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles)and dissolved in 3.8 ml of ethanol under nitrogen. Next added 0.1 g ofPd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas.Stirred for 48 h. After filtering off the catalyst and removing thesolvent by rotary evaporation 39 was isolated by column chromatography(0.16 g) using 90/10 hexane ethyl acetate and gradually increasing themobile phase to 70/30 hexane/ethyl acetate. The product wascharacterized by NMR and mass spectra.

[0307] Step 2. (3a,4a,5a)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(40) and (3a,4b,5b)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(41)

[0308] A 2-neck, 25 ml round bottomed flask with stir bar was chargedwith 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen.Cool to −10° C. by means of a salt/water bath. Slowly add 0.113 g ofpotassium tert butoxide (0.335 mmole). After 15 min at −10° C. all ofthe starting material was consumed by TLC and only the two isomers 40and 41 were observed. Next added 5 ml of chilled 10% HCl and stirred at−10° C. for 5 min. Transferred to a separatory funnel and extract withether. Dried over sodium sulfate. Proton NMR of the dried product (0.143g) indicated only the presence of the two isomers 40 and 41. The twoisomers were separated by silica gel chromatography using 90/10 hexaneethyl acetate and gradually increasing the mobile phase to 70/30hexane/ethyl acetate. 40 (53.2 mg); 41(58.9 mg).

Example 24

[0309]

[0310] Quaternization of Amine Substrates 40 and 41

[0311] Amine products such as 40 and 41 can be readily alkylated toquaternary salts by reaction with alkyl halides. For example 40 in DMFwith 5 equivalents of methyl iodide in the presence of 2,6 dimethyllutidine produces the dimethylhexylamino quaternary salt.

Example 25

[0312]

[0313] (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(42)

[0314] In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d 0.67 g ofmercuric triflate were dissolved in 20 ml of dry methylene chloride withstirring. Next 0.34 g of Iodine was added and the solution was stirredat room temperature for 30 h. The reaction was then diluted with 50 mlmethylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10ml of saturated KI; and dried over sodium sulfate. See Tetrahedron, Vol.50; No. 17, pp 5139-5146 (1994) Bachki, F. Et al. Mass spectrumindicated a mixture of 6d, mono iodide 42 and a diiodide adduct. Themixture was separated by column chromatography and 42 was characterizedbt NMR and mass spectra.

Example 26

[0315]

[0316] (3a,4b,5b)3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(43)

[0317] A 0.1 g sample of 42 (0.212 mmole), 2.5 ml dry methanol, 38 μltriethylamine (0.275 mmole), 0.3 ml toluene and 37 mg of palladiumchloride (0.21 mmole) was charged to a glass lined mini reactor at 300psi carbon monoxide. The reaction was heated at 100° C. overnight. Thecatalyst was filtered and a high yield of product was isolated.

[0318] The product was characterized by NMR and mass spectra.

[0319] Note the ester functionalized product 43 can be converted to thefree acid by hydrolysis.

Example 27

[0320] (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(48), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(49)

[0321] Step 1. 2-Mercapto-5-methoxybenzophenone (50)

[0322] Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 Nn-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g ofbenzonitrile in 600 ml cyclohexane according to the procedure in WO93/16055 gave 73.2 g of brown oil which was kugelrohr distilled toremove 4-methoxythiophenol and gave 43.86 g of crude 50 in the potresidue.

[0323] Step 2. 2-((2-Benoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal(51)

[0324] Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml ofdiglyme according to the procedure for the preparation of 2 gave 10.5 gof crude product which was purified by HPLC (5% ethyl acetate-hexane) togive 1.7 g (22%) of 51.

[0325] Step 3.2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)-2-ethyl-hexanal (52)

[0326] A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylenechloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA accordingto the procedure of step 2 of procedure A in example 18 gave 1.16 g(90%) of 52 as a yellow oil.

[0327] Step 4.2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (53)

[0328] Hydrogenation of 1.1 g of 52 according to the procedure of step 3of procedure A of example 18 gave 53 as a yellow oil (1.1 g).

[0329] Step 5. (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(48), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(49)

[0330] A solution of 1.1 g of 53, 0.36 g or potassium t-butoxide and 25ml of anhydrous THF was held at reflux for 2 h and worked up as in step4 of procedure A of example 18 to give 1.07 g of a crude product whichwas purified by HPLC to give 40 mg (4%) of 48 as crystals; mp 153-154°C. and 90 mg (8%) of 49 as solid, mp 136-140° C.

Example 28

[0331]

[0332] 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane (57)

[0333] Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54)

[0334] To a cold (0° C. mixture of 100 g (0.891 mole) ofcyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml ofmethanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. Thereaction mixture was stirred at room temperature over 48 then wasevaporated to remove methanol. The reaction mixture was diluted withwater and extracted with methylene chloride. The organic layer waswashed with water, brine, and dried over sodium sulfate and concentratedunder vacuum to give 75 g (59.7%) of thick oil. Proton NMR and massspectra were consistent with the product.

[0335] Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde (55)

[0336] To a cold (0° C. mixture of alcohol 54 (75 g, 0.54 mole) and65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylenechloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 mlof methylene chloride. The reaction mixture was stirred at roomtemperature for 18 h then quenched with water, acidified with conc. HCland extracted with methylene chloride. The organic layer was washed withwater, brine, and dried over sodium sulfate and concentrated undervacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectrawere consistent with the product.

[0337] Step 3. 1-((2-Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde(56)

[0338] A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g(0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml ofdiglyme was stirred and held at reflux for 24 h. The mixture was cooled,poured into dil. HCl and extracted with methylene chloride. The organiclayer was washed with 10% NaOH, water, brine, and dried over sodiumsulfate and concentrated under vacuum to remove excess diglyme. This waspurified by silica gel flush column (5% EtOAc: Hexane) and gave 18.6 g(75.9%) of yellow oil. Proton NMR and mass spectra were consistent withthe product.

[0339] Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane(57)

[0340] To a mixture of 6.19 g of zinc dust and 100 ml of dry DEE wasadded TiCl₃ (16.8 g, 0.108 mole). The reaction mixture was heated toreflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 mlof DME was added dropwise to the reaction mixture in 1 h and the mixturewas held at reflux for 18 h. The mixture was cooled, poured into waterand extracted with ether. The organic layer was washed with water,brine, and dried over sodium sulfate, filtered through celite andconcentrated under vacuum. The residue was purified by HPLC (10% EtOAc:Hexane) to give 4.6 g (64%) of white solid, mp 90-91° C. Proton andcarbon NMR and mass spectra were consistent with the product.

Example 29

[0341]

[0342]8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1′-cyclohexane)-4,4-dioxide(5B)

[0343] To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform undernitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise withspatula. The reaction was held at reflux for 18 h and washed with 10%NaOH(3×), water, brine, and dried over sodium sulfate and concentratedunder vacuum to give 5 g of crude product. This was recrystallized fromHexane/EtoAc to give 4.31 g (81%) of yellow solid, mp 154-155° C. Protonand carbon NMR and mass spectra were consistent with the product.

Example 30

[0344]

[0345] trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydrospiro(benzothiepine-3,1′-cyclohexane)-1,1-dioxide (59)

[0346] A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol, 10 ml ofmethylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with70 psi hydrogen for 3 h at room temperature. The crude reaction slurrywas filtered through Celite and evaporated to dryness. The residue waspurified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The firstfraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMRshowed this was a trans isomer. The second fraction gave 200 mg of solidwhich was impure cis isomer.

Example 31

[0347]

[0348] cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydrospiro(benzothiepine-3,1′-cyclohexane)-1,1-dioxide (60)

[0349] To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH₂Cl₂, wasadded 8 g of 50% NaOH and one drop of Aliquat-336(methyltricaprylylammonium chloride) phase transfer catalyst. Thereaction mixture was stirred for 10 h at room temperature. Twenty g ofice was added to the mixture and the mixture was extracted with CH₂Cl₂(3×10 ml) washed with water, brine and dried over MgSO₄ and concentratedin vacuo to recover 0.15 g of crude product. This was recrystallizedfrom Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Protonand carbon NMR and mass spectra were consistent with the product.

Example 32

[0350]

[0351] (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61),and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62)

[0352] To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml ofanhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide.The reaction mixture was stirred at room temperature for 18 h andquenched with 10 ml of 10% HCl. The organic was extracted into methylenechloride. The methylene chloride extract was dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by HPLC (2%EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62in the third fraction. Proton NMR and mass spectra were consistent withthe assigned structures.

Example 33

[0353]

[0354] (3a,4a,5a)3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(63) and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64)

[0355] An autoclave was charged with 200 mg of 37 in 40 cc ethanol and0.02 g 10% Pd/C. After purging with nitrogen the clave was charged with100 psi hydrogen and heated to 55 C. The reaction was monitored by TLCand mass spec and allowed to proceed until all of 37 was consumed. Afterthe reaction was complete the catalyst was filtered and the solvent wasremoved in vacuo and the only observable product was amine 63. This sameprocedure was used to produce 64 from 38.

Example 34

[0356]

[0357] (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(65), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(66).

[0358] Alkylation of e-methoxyphenol with 3-methoxybenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(3′-methoxybenzyl)phenol in 35% yield. This material wasconverted to compound 65, mp 138.5-141.5° C., and compound 66, mp115.5-117.5° C., by the procedure similar to that in Example 18 methodB.

Example 35

[0359] (3a,4a,5a)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(67), and (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(68).

[0360] Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzylchloride according to the procedure described in J. Chem. Soc. 2431(1958) gave 4-methoxy-2-(3′-(trifluoromethyl)benzyl)phenol. Thismaterial was converted to compound 67, mp 226.5-228° C., and compound68, mp 188-190° C., byu the procedure similar to that in Example 18method B.

Example 36

[0361]

[0362] (3a,4a,5a)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(69), and (3a,4b,5b)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(70).

[0363] Alkylation of 4-methoxyphenol with 4-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(4′-fluorobenzyl)phenol. This material was converted tocompound 69 and compound 70 by the procedure similar to that in Example18 method B.

Example 37

[0364]

[0365] (3a,4a,5a)3-Butyl-3-ethyl-5-(3′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(71), and (3a,4b,5b)3-Butyl-3-ethyl-5-(3′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(72).

[0366] Alkylation of 4-methoxyphenol with 3-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(3′-fluorobenzyl)phenol. This material was converted tocompound 71 and compound 72 by the procedure similar to that in Example18 method B.

Example 38

[0367]

[0368] (3a,4a,5a)3-Butyl-3-ethyl-5-(2′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(73), and (3a,4b,5b)3-Butyl-3-ethyl-5-(2,-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(74)

[0369] Alkylation of 4-methoxyphenol with 2-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(2′-fluorobenzyl)phenol. This material was converted tocompound 73 and compound 74 by the procedure similar to that in example18 method B.

Example 39

[0370]

[0371] (3a,4a,5a)3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3′methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(75), and (3a,4b,5b)3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(76).

[0372] Alkylation of 4-bromophenol with 3-methoxybenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-bromo-2-(3′-methoxybenzyl)phenol. This material was converted tocompound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by theprocedure similar to that in Example 18 method B.

Example 40

[0373]

[0374] (3a,4a,5a)3-Butyl-3-ethyl-7-fluoro-5-(4′-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(77), and (3a,4b,5b)3-Butyl-3-ethyl-7-fluoro-5-(4′-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(78).

[0375] Alkylation of 4-fluorophenol with 4-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-fluoro-2-(4′-fluorobenzyl)phenol. This material was converted tocompound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by theprocedure similar to that in Example 18 method B.

Example 41

[0376]

[0377] (3a,4a,5a)3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(79), and (3a,4b,5b)3-Butyl-3-ethyl-7-fluoro-40hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(80).

[0378] Alkylation of 4-fluorophenol with 3-methoxybenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-fluoro-2-(3 -methoxybenzyl)phenol. This material was converted tocompound 79, as a solid and compound 80, mp 153-155° C., by theprocedure similar to that in Example 18 method B.

Example 42

[0379]

[0380] (3a,4b,5b)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methylthio-2,34,5-tetrahydrobenzothiepine-1,1-dioxide (81).

[0381] A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) ofsodium methanethiolate and 15 ml of anhydrous DMF was stirred at roomtemperature for 16 days. The reaction mixture was dilute with ether andwashed with water and brine and dried over M_(g)SO₄. The ether solutionwas concentrated in vacuo. The residue was purified by HPLC (20% ethylacetate in hexanes). The first fraction was impure (3a,4a,5a)3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.The second fraction was compound 81, mp 185-186.5° C.

Example 43

[0382]

[0383] (3a,4b,5b)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(82).

[0384] A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml ofpyrrolidine was held at reflux for 1 h. The reaction mixture was dilutedwith ether and washed with water and brine and dried over M_(g)SO₄. Theether solution was concentrated in vacuo. The residue was crystallizedfrom ether-hexanes to give compound 82, mp 174.5-177° C.

Example 44

[0385]

[0386] (3a,4b,5b)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-morpholinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(83).

[0387] A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol)of morpholine was held at reflux for 2 h and concentrated in vacuo. Theresidue was diluted with ether (30 ml) and washed with water aid brineand dried over M_(g)SO₄. The ether solution was concentrated in vacuo.The residue was recrystallized from ether-hexanes to give compound 83,mp 176.5-187.5° C.

Example 45

[0388] (3a,4a,5a)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(84), and (3a,4b,5b)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(85).

[0389] Alkylation of 4-methylphenol with 4-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methyl-2-(4′-fluorobenzyl)phenol). This material was converted tocompound 84 and compound 85 by the procedure similar to that in Example18 method B.

Example 46

[0390]

[0391] (3a,4b,5b)3-Butyl-3-ethyl-4-hydroxy-5-(4′-hydroxyphenyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(86), and (3a,4b,5b)3-Butyl-3-ethyl-4,7-dihydroxy-5-(4′-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(87).

[0392] To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml ofmethylene chloride was added 1.7 g (6.78 mmol) of born tribromide. Thereaction mixture was cooled to −78° C. and was stirred for 4 min. Anadditional 0.3 ml of boron tribromide was added to the reaction mixtureand the reaction mixture was stirred at −78° C. for 1 h and quenced with2 N HCl. The organic was extracted into ether. The ether layer waswashed with brine, dried over M_(g)SO₄, and concentrated in vacuo. Theresidue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes).The first fraction was 0.11 g of compound 86 as a white solid, mp171.5-173° C. The second fraction was crystallized from chloroform togive 0.04 g of compound 87 as a white solid, mp 264° C. (dec).

Example 47

[0393]

[0394] (3a,4b,5b)3-Butyl-3-ethyl-4,7-dihydroxy-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(88).

[0395] Reaction of compound 70 with excess boron tribromide at roomtemperature and worked up as in Example 46 gave compound 88 after anHPLC purification.

Example 48

[0396]

[0397] (3a,4b,5b)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-azetidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(89).

[0398] A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo.The residue was diluted with ether (30 ml) and washed with water andbrine and dried over MgSO4. The ether solution was concentrated on asteam bath. The separated crystals were filtered to give 0.136 g of 89as prisms, mp 196.5-199.5° C.

Example 49

[0399]

[0400] (3a,4a,5a)3-Butyl-3-ethyl-5-(3′-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(90). (3a,4b,5b)3-Butyl-3-ethyl-5-(3′-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(91).

[0401] A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol)of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60°C. for 2 h. An additional 1.4 mmol of sodium methanethiolate was addedto the reaction mixture and the mixture was stirred at 60° C. for anadditional 2 h. The reaction mixture was triturated with 100 ml of waterand extracted methylene chloride. The methylene chloride water mixturewas filtered through Celite and the methylene chloride layer was driedover M_(g)SO₄ and concentrated in vacuo. The first fraction (0.1 g) wascompound 90, mp 117-121° C. The second fraction (0.16 g) was compound91, mp 68-76° C.

Example 50

[0402] Preparation of polyethyleneglycol functionalized benzothiepine A.

[0403] A 50 ml rb flash under a nitrogen atmosphere was charged with0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway,SW, Huntsville, Ala. 35801), 0.055 g Compound No. 136, 0.326 C_(g)CO₃and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C. for 5days and then the solution was filtered to remove salts. Next, theacetonitrile was removed under vacuum and the product was dissolved inTHF and then precipitated by addition of hexane. The polymer precipitatewas isolate by filtration from the solvent mixture (THF/hexane). Thisprecipitation procedure was continued until no Compound No. 136 wasdetected in the precipitated product (by TLC SiO2). Next, the polymerprecipitate was dissolved in water and filtered and the water solublepolymer was dialyzed for 48 hours through a cellulose dialysis tube(spectrum® 7, 45 mm×0.5 ft, cutoff, 1,000 MW). The polymer solution wasthen removed from the dialysis tube and lyophilized until dried. The NMRwas consistent with the desired product A and gel permeationchromatography indicated the presence of a 4500 MW polymer and alsoverified that no free Compound No. 136 was present. This material wasactive in the IBAT in vitro cell assay.

Example 51

[0404] Preparation of Compound 140

[0405] A 2-necked 50 ml round bottom Flask was charged with 0.42 g ofTres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres, MW 3400]purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW,Huntsville, Ala. 35801), 0.1 potassium carbonate, 0.100 g of CompoundNo. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27° C. TLC indicatedthe disappearance of the starting Compound No. 111. The solution wastransferred to a separatory funnel and diluted with 50 cc methylenechloride and then extracted with water. The organic layer was evaporatedto dryness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, thepolymer was dissolved in water and then dialyzed for 48 hours at 40° C.through a cellulose dialysis tube (spectrum® 7, 45 mm×0.5 ft, cutoff1,000 MW). The polymer solution was then removed from the dialysis tubeand lyophilized until dried 0.341 g). N was consistent with the desiredproduct B.

Example 52

[0406]

[0407] A 10 cc vial was charged with 0.21 g of Compound No. 136 (0.5mmoles), 0.17 g (1.3 mmoles) potassium carbonate, 0.6 g (1.5 mmoles) of1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirredfor 4 days at room temperature and then worked up by washing withether/water. The ether layer was stripped to dryness and the desiredproduct Compound No. 134 was isolated or a silica gel column using 80/20hexane ethyl acetate.

Example 53

[0408]

Example 54

[0409]

[0410] A two necked 25 ml round bottom Flask was charged with 0.5 g(1.24 mmoles) of 69462, 13 mls of anhydrous DMF. 0.055 g of 60% NaHdispersion and 0.230 g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at10° C. under nitogen. Next, the reaction was slowly heated to 40° C.After 14 hours all of the Compound No. 113 was consumed and the reactionwas cooled to room temperature and extracted with ether/water. The etherlayer was evaporated to dryness and then chromatographed on Silicage(80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) wascharacterized by NMR and mass spec.

Example 55

[0411]

[0412] In a 50 ml round bottom Flask, add 0.7 g (1.8 mmoles) of CompoundNo. 136, 0.621 g of potassium, carbonate, 6 ml DMF, and 0.33 g of1,2-Bis (2-iodoethoxylethane). Stir at 40° C. under nitrogen for 12hours. The workup and isolation was the same procedure for Compound No.112.

Examples 56 and 57 (Compound Nos. 131 and 137)

[0413] The compositions of these compounds are shown in Table 3.

[0414] The same procedure as for Example 53 except appropriatebenzothiepine was used.

Example 58 (Compound No. 139)

[0415] The composition of this compound is shown in Table 3. Sameprocedure as for Example 55 with appropriate benzothiepine 1,6diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].

Example 59 (Compound No. 101)

[0416]

[0417] This compound is prepared by condensing the 7-NH₂ benzothiepinewith the 1,12-dodecane dicarboxylic acid or acid halide.

Example 60 (Compound No. 104)

[0418]

[0419] 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane andtrifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32.Reaction of 32 with lithium sulfide followed by reacting the resultingsulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation ofXXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (seeScheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100psi hydrogen and 55 C. for 12 hours catalyzed by palladium on carbon inthe same reaction vessel yields the substituted dimethylamine derivativeXXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixtureof substituted amino derivatives of this invention Compound No. 104.

Example 61

[0420]

[0421] A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml ofanhydrous acetonitrile. Heat to 50° C. for 4 days. The quat. SaltCompound No. 192 was isolated by concentrating to 1 cc acetonitrile andthen precipitating with diethyl ether.

Example 62

[0422]

[0423] A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolvedin 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and thentrimethylamine was bubbled through the solution for 5 minutes at 0° C.and then capped and warmed to room temperature. The reaction was stirredovernight and the desired product was isolated by removing solvent byrotary evaporation.

Example 63 (Compound No. 295)

[0424]

[0425] Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of acetonitrileat 0° C. was reacted with 0.248 mmoles (0.10 g) of Compound No. 54 in2.5 cc of acetonitrile at 0° C. Next, 0.(980 g 2.48 mmoles) of 1,2-Bis[2-iodoethoxylethane]. After warming to room temperature, stir for 14hours. The product was isolated by column chromatography.

Example 64 (Compound No. 286)

[0426]

[0427] Following a procedure similar to the one described in Example 86,infra (see Compound No. 118), the title compound was prepared andpurified as a colorless solid; mp 180-181° C.; ¹H NMR (CHCl₃) δ 0.85 (t,J=6 Hz, 3H_(—), 0.92 (t, J=6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m,1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, J_(AB)=15 Hz, Δv=42Hz, 2H), 4.20 (d, J=8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H),6.68 (s, 1H), 7.29-7.51 (m, 10H), 7.74 (d, J=8 Hz, 1H) 8.06 (d, J=8 Hz,1H). FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001, found 494.1993.Anal. Calcd. for C₂₈H₃₁NO₅S: C, 68.13; H, 6.33; N, 2.84. Found: C,68.19; H, 6.56; N, 2.74.

Example 65 (Compound No. 287)

[0428]

[0429] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified as a colorless solid: mp 245-246° C., ¹H NMR (CDCl₃) δ 0.84 (t,J=6 Hz, 3H), 0.92 (t, J=6 Hz, 3H), 1.28, (d, J=8 Hz, 1H), 1.32-1.42 (m,1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB,J_(AB)=15 Hz, Δv=42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J=8 Hz, 1H), 5.49(s, 1H), 5.95 (s, 1H), 6.54 (d, J=7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d,J=8 Hz, 1H); ESMS 366 (M+Li). Anal. Calcd. for C₂₀F₂₅NO₃S: C, 66.82; H,7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.

Example 66 (Compound No. 288)

[0430]

[0431] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified by silica gel chromatography to give the desired product as acolorless solid: mp 185-186° C.; ¹H NMR (CDCl₃) δ1.12 (s, 3H), 1.49 (s,3H), 3.00 (d, J=15 Hz, 1H), 3.28 (d, J=15 Hz, 1H), 4.00 (s, 1H), 5.30(s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J=2.1, 8.4 Hz, 1H),7.31-7.52 (m, 5H), 7.89 (d, J=8.4 Hz, 1H). MS (FAB+) (M+H) m/z 332.

Example 67 (Compound No. 289)

[0432]

[0433] Following a procedure similar to the one described in Example 89(see Compound No. 121), the title compound was prepared and purified bysilica gel chromatography to give the desired product as a white solid:mp 205-206° C.; ¹H NMR (CDCl₃) δ 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H),2.15 (m, 1H), 3.02 (d, J=15.3 Hz, 2H), 3.15 (d, J=15.1 Hz, 2H), 3.96 (s,br, 2H), 4.14 (d, J=7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J=2.2, 1H), 6.54(dd, J=8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J=8.5 Hz, 1H). MS(FAB): m/z 388 (M+H).

Example 68 (Compound No. 290)

[0434]

[0435] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified as a colorless solid: mp=96-98° C., ¹H NMR (CDCl₃) δ 0.92 (t,J=7 Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (t, J=8 Hz, 1H), 3.09 (AB,J_(AB)=18 Hz, Δv=38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J=7 Hz, 1H), 5.51(s, 1H), 5.94 (s, 1H), 6.56 (d, J=9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d,J=8 Hz, 1H); FABMS m/z 416 (M+H).

Example 69

[0436]

[0437] Following a procedure similar to the one described in Example 86,infra (see Compound No. 118), the title compound was prepared andpurified as a colorless solid: ¹H NMR (CDCl₃) δ 0.91 (t, J=7 Hz, 6H),1.02-1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J=8 Hz, 1H), 3.12 (AB,J_(AB)=18 Hz, Δv=36 Hz, 2H), 4.18 (d, J=7 Hz, 1H), 5.13 (s, 2H), 5.53(s, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J=9Hz, 1H), 8.03 (d, J=8 Hz, 1H); ESMS m/z 556 (M+Li).

Example 70 (Compound No. 292)

[0438]

[0439] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified as a colorless solid: mp=111-112.5° C., ¹H NMR (CDCl₃) δ 0.90(t, J=8 Hz, 6H), 1.03-1.50 (m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J=12Hz, 2H), 3.07 (AB, J_(AB)=15 Hz, Δv=45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s,1H), 5.91 (s, 1H), 6.55 (d, J=9 Hz, 1H), 7.10 (t, J=7 Hz, 2H), 7.46 (t,J=6 Hz, 2H), 7.87 (d, J=9 Hz, 1H).

Example 71 (Compound No. 293)

[0440]

[0441] During the preparation of Compound No. 290 from Compound No. 291using BBr₃, the title compound was isolated: ¹H NMR (CDCl₃) δ 0.85 (t,J=6 Hz, 6H), 0.98-1.60 (m, 10H), 1.50-1.66 (m, 2H), 2.16 (t, J=8 Hz,1H), 3.04 (AB, J_(AB)=15 Hz, Δv=41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H),5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d, J=9 Hz, 1H), 7.12 (d, J=8 Hz, 2H),7.16-7.26 (m, 10H), 7.83 (d, J=8 Hz, 1H); ESMS m/z 512 (M+Li).

Example 72 (Compound No. 294)

[0442] Following a procedure similar to the one described in Example 60(Compound No. 104), the title compound was prepared and purified as acolorless solid: ¹H NMR (CDCl₃) δ 0.90 (t, J=6 Hz, 6H), 1.05-1.5 (m,9H), 1.60-1.70 (m, 1H), 2.24 (t, J=8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB,J_(AB)=15 Hz, Δv=42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 4H), 5.93 (s,1H), 6.94 (d, J=9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J=8 Hz, 2H), 7.87(d, J=9 Hz, 1H); ESMS m/z 444 (M+H).

[0443] Structures of the compounds of Examples 33 to 72 are shown inTables 3 and 3A.

Examples 73-79, 87, 88 and 91-102

[0444] Using in each instance a method generally described in those ofExamples 1 to 72 appropriate to the substituents to be introduced,compounds were prepared having the structures set forth in Table 3. Thestarting materials illustrated in the reaction schemes shown above werevaried in accordance with principles of organic synthesis well known tothe art to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzoring (R^(x))

[0445] Structures of the the compounds produced in Examples 73-102 areset forth in Tables 3 and 3A.

Examples 80-84

[0446] Preparation of 115, 116, 111, 113

[0447] Preparation of 4-chloro-3-[4-methoxyphenylmethyl]-nitrobenzene.

[0448] In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphoruspentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly add60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole). Stir at room tempovernight under N2 then heat 1 hr at 50C.

[0449] Remove chlorobenzene by high vacuum. Wash residue with hexane.Dry wt=55.5 gms.

[0450] In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole)from above with 100 mls anisole (about 3.4 eq). Chill solution with icebath while purging with N2. Slowly add 40.3 g aluminum chloride (1.2 eq0.3 mole). Stir under N₂ for 24 hrs.

[0451] After 24 hrs, the solution was poured into 300 mls 1N HCl soln.(cold). Stir this for 15 min. Extract several times with diethyl ether.Extract organic layer once with 2% aqueous NaOH then twice with water.Dry organic layer with MgSO4, dry an vac line. Solid is washed well withether and then ethanol before drying. Wt=34.57 g (mixture of meta, orthoand para). Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 Cl12.15 12.16

[0452] With the next step of the reduction of the ketone withtrifluoromethane sulfonic aid and triethyl silane, crystallization withethyl acetate/hexane affords pure4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

[0453] 4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reactedas specified in the synthesis of 117 and 118 from2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can besynthesized. Compounds 111 and 113 can be synthesized from the procedureused to prepare compound 121.

[0454] Compound 114 can be prepared by reaction of 116 with ethylmercaptan and aluminum trichloride.

Examples 85 and 86

[0455] Preparation of 117 and 118

[0456] 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane andtrifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32.Reaction of 32 with lithium sulfide followed by reacting the resultingsulfide with mesylate IV gives sulfide-aldehyde XXII. Oxidation of XXIIIwith 2 equivalents of MCPSA yields sulfone-aldehyde XXIII. Oxidation ofXXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (seeScheme 5).

[0457] The sulfone-aldehyde (31.8 g) was dissolved in ethanol/tolueneand placed in a parr reactor with 100 ml toluene and 100 ml of ethanoland 3.2 g of 10% Pd/C and heated to 55 C. and 100 psi of hydrogen gasfor 14 hours. The reaction was then filtered to remove the catalyst. Theamine product (0.076 moles, 29.5 g) from this reaction was then reactedwith benzyl chloroformate (27.4 g) in toluene in the presence of 35 g ofpotassium carbonate and stirred at room temperature overnight. Afterwork up by extraction with water, the CBZ protected amine product wasfurther purified by precipitation from toluene/hexane.

[0458] The CBZ protected amine product was then reacted with 3equivalents of potassium t-butoxide in THF at O C to yield compounds 117and 118 which were separated by silica gel column chromatography.

Examples 89 and 90

[0459] Preparation of 121 or 122

[0460] Compound 118 (0.013 moles, 6.79 g) is dissolved in 135 ml of drychloroform and cooled to −78 C., next 1.85 ml of boron tribromide (4.9g) was added and the reaction is allowed to warm to room temperature.Reaction is complete after 1.5 hours. The reaction is quenched byaddition of 10% potassium carbonate at 0 C. and extract with ether.Removal of ether yields compound 121. A similar procedure can be used toproduce 122 from 117.

Examples 93-96

[0461] Compounds 126, 127, 128 and 129 as set forth in Table 3 wereprepared substantially in the manner described above for compounds 115,116, 111 and 113, respectively, except that fluorobenzene was used as astarting material in place of anisole. TABLE 3 Specific compounds(#102-111, 113-130, 132-134, 136, 138, 142-144, 262-296)

Ex. Cp # R¹ R² R³ R⁴ R⁵ R⁶ (R^(x))q 61 102 Et— n-Bu— HO— H— Ph— H— I⁻,7- (CH₃)₃N⁺— 73 103 n-Bu— Et— HO— H— Ph— H— I⁻, 7- (CH₃)₃N⁺— 60 104 Et—n-Bu— HO— H— Ph— H— 7-(CH₃)₂N— 74 105 Et— n-Bu— HO— H— Ph— H— 7-CH₃SO₂NH— 75 106 Et— n-Bu— HO— H— Ph— H— 7-Br-CH₂— CONH— 76 107 n-Bu—Et— HO— H— p-n-C₁₀H₂₁ —O— H— 7-NH₂— Ph— 77 108 Et— n-Bu— HO— H— Ph— H—7- C₅H₁₁CONH— 78 109 Et— n-Bu— HO— H— p-n-C₁₀H₂₁ —O— H— 7-NH₂— Ph— 79110 Et— n-Bu— HO— H— Ph— H— 7-CH₃CONH— 80 111 n-Bu— Et— HO— H— p-HO—Ph—H— 7-NH₂— 81 113 Et— n-Bu— HO— H— p-HO—Ph— H— 7-NH₂— 82 114 Et— n-Bu—HO— H— p-CH₃O—Ph— H— 7-NH₂— 83 115 n-Bu— Et— HO— H— p-CH₃O—Ph— H—7-NH—CBZ 84 116 Et— n-Bu— HO— H— p-CH₃O—Ph— H— 7-NH—CBZ 85 117 n-Bu— Et—HO— H— Ph— H— 7-NH—CBZ 86 118 Et— n-Bu— HO— H— Ph— H— 7-NH—CBZ 87 119Et— n-Bu— HO— H— Ph— H— 7-NHCO₂-t- Bu 88 120 n-Bu— Et— HO— H— Ph— H—7-NHCO₂-t- Bu 89 121 Et— n-Bu— HO— H— Ph— H— 7-NH₂— 90 122 n-Bu— Et— HO—H— Ph— H— 7-NH₂— 91 123 Et— n-Bu— HO— H— Ph— H— 7-n-C₆H₁₃ — NH— 92 124n-Bu— Et— HO— H— Ph— H— 7-n-C₆H₁₃ — NH— 62 125 Et— n-Bu— HO— H— Ph— H—I⁻, 8- (CH₃)₃N⁺(CH₂CH₂O)₃— 93 126 n-Bu— Et— HO— H— p-F—Ph— H— 7-NH—CBZ94 127 n-Bu— Et— HO— H— p-F—Ph— H— 7-NH₂— 95 128 Et— n-Bu— HO— H—p-F—Ph— H— 7-NH—CBZ 96 129 Et— n-Bu— HO— H— p-F—Ph— H— 7-NH₂— 97 130 Et—n-Bu— HO— H— Ph— H— I⁻, 8- (CH₃)₃N⁺C₆H₁₂O— 98 132 Et— n-Bu— HO— H— Ph—H— 8-phthal- imidyl- C₆H₁₂O— 99 133 Et— n-Bu— HO— H— Ph— H— 8-n-C₁₀H₂₁—52 134 Et— n-Bu— HO— H— Ph— H— 8-I—(C₂H₄O)₃— 100 136 Et— n-Bu— HO— H—Ph— H— 8-HO— 101 138 n-Bu— Et— HO— H— Ph— H— 8-CH₃CO₂— 49 90 Et— n-Bu—H— HO— H— m-CH₃O—Ph— 7-CH₃S— 49 91 Et— n-Bu— HO— H— m-CH₃O—Ph— H—7-CH₃S— 48 89 Et— n-Bu— HO— H— p-F—Ph— H— 7-(N)- azetidine 34 66 Et—n-Bu— HO— H— m-CH₃O—Ph— H— 7-CH₃O— 34 65 Et— n-Bu— H— HO— H— m-CH₃O—Ph—7-CH₃O— 35 68 Et— n-Bu— HO— H— m-CF₃—Ph— H— 7-CH₃O— 35 67 Et— n-Bu— H—HO— H— m-CF₃—Ph— 7-CH₃O— 46 87 Et— n-Bu— HO— H— m-HO—Ph— H— 7-HO— 46 86Et— n-Bu— HO— H— m-HO—Ph— H— 7-CH₃O— 36 70 Et— n-Bu— HO— H— p-F—Ph— H—7-CH₃O— 36 69 Et— n-Bu— H— HO— H— p-F—Ph— 7-CH₃O— 47 88 Et— n-Bu— HO— H—p-F—Ph— H— 7-HO— 39 76 Et— n-Bu— HO— H— m-CH₃O—Ph— H— 7-Br— 39 75 Et—n-Bu— H— HO— H— m-CH₃O—Ph— 7-Br— 40 77 Et— n-Bu— H— HO— H— p-F—Ph— 7-F—40 78 Et— n-Bu— HO— H— p-F—Ph— H— 7-F— 41 79 Et— n-Bu— H— HO— H—m-CH₃O—Ph— 7-F— 41 80 Et— n-Bu— HO— H— m-CH₃O—Ph— H— 7-F— 37 72 Et—n-Bu— HO— H— m-F—Ph— H— 7-CH₃O— 38 73 Et— n-Bu— H— HO— H— o-F—Ph—7-CH₃O— 37 71 Et— n-Bu— H— HO— H— m-F—Ph— 7-CH₃O— 38 74 Et— n-Bu— HO— H—o-F—Ph— H— 7-CH₃O— 42 81 Et— n-Bu— HO— H— p-F—Ph— H— 7-CH₃S— 45 85 Et—n-Bu— HO— H— p-F—Ph— H— 7-CH₃— 45 84 Et— n-Bu— H— HO— H— p-F—Ph— 7-CH₃—44 83 Et— n-Bu— HO— H— p-F—Ph— H— 7-(N)- morpholine 43 82 Et— n-Bu— HO—H— p-F—Ph— H— 7-(N)- pyrrolidine 64 286 Et— Et— HO— H— Ph— H— 7-NH—CBZ65 287 Et— Et— HO— H— Ph— H— 7-NH₂— 66 288 CH_(3—) CH₃— HO— H— Ph— H—7-NH₂— 67 289 n-C₃H₇— n-C₃H₇— HO— H— Ph— H— 7-NH₂— 68 290 n-Bu— n-Bu—HO— H— Ph— H— 7-NH₂— 69 292 n-Bu— n-Bu— HO— H— Ph— H— 7-NH—CBZ 70 292n-Bu— n-Bu— HO— H— p-F—Ph— H— 7-NH₂— 71 293 n-Bu— n-Bu— HO— H— Ph— H—7-PhCH₂N— 72 294 n-Bu— n-Bu— HO— H— Ph— H— 7-(CH₃)₂N— 63 295 Et— n-Bu—HO— H— p-I— H— 7-NH₂— (C₂H₄O)₃—Ph— 102 296 Et— n-Bu— HO— H— I⁻, p- H—7-NH₂— (CH₃)₃N⁺(C₂H₄O)₃—Ph—

[0462] TABLE 3A Bridged Benzothiephenes (#101, 112, 131, 135, 137,139-141)

CPD #101 (Ex. 59)

CPD #112 (Ex. 53)

CPD #131 (Ex. 56)

CPD #135 (Ex. 55)

CPD #137 (Ex. 57)

CPD #139 (Ex. 58)

CPD #140 (Ex. 51) 3400 MW polyethyleneglycol bridge

CPD #141 (Ex. 50)

Examples 104-231

[0463] Using in each instance a method generally described in those ofExamples 1 to 72 appropriate to the substituents to be introduced,including where necessary other common synthesis expedients well knownto the art, compounds are prepared having the structures set forth inTable 4. The starting materials illustrated in the reaction schemesshown above are varied in accordance with principles of organicsynthesis well known to the art in order to introduce the indicatedsubstituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in theindicated position on the benzo ring (R^(x)). TABLE 4 Alternativecompounds #1 (#302-312, 314-430)

Cpd # R⁵ (R^(x))q 302 p-F—Ph— 7-(1-aziridine) 303 p-F—Ph— 7-EtS— 304p-F—Ph— 7-CH₃S(O)— 305 p-F—Ph— 7-CH₃S(O)₂— 306 p-F—Ph— 7-PhS— 307p-F—Ph— 7-CH₃S— 9-CH₃S— 308 p-F—Ph— 7-CH₃O— 9-CH₃O— 309 p-F—Ph— 7-Et—310 p-F—Ph— 7-iPr— 311 p-F—Ph— 7-t-Bu— 312 p-F—Ph— 7-(1-pyrazole)- 314m-CH₃O—Ph 7-(1-azetidine) 315 m-CH₃O—Ph— 7-(1-aziridine) 316 m-CH₃O—Ph—7-EtS— 317 m-CH₃O—Ph— 7-CH₃S(O)— 318 m-CH₃O—Ph— 7-CH₃S(O)₂— 319m-CH₃O—Ph— 7-PhS— 320 m-CH₃O—Ph— 7-CH₃S— 9-CH₃S— 321 m-CH₃O—Ph— 7-CH₃O—9-CH₃O— 322 m-CH₃O—Ph— 7-Et— 323 m-CH₃O—Ph— 7-iPr— 324 m-CH₃O—Ph—7-t-Bu— 325 p-F—Ph— 6-CH₃O— 7-CH₃O— 8-CH₃O— 326 p-F—Ph— 7-(1-azetidine)9-CH₃— 327 p-F—Ph— 7-EtS— 9-CH₃— 328 p-F—Ph— 7-CH₃S(O)— 9-CH₃— 329p-F—Ph— 7-CH₃S(O)₂— 9-CH₃— 330 p-F—Ph— 7-PhS— 9-CH₃— 331 p-F—Ph— 7-CH₃S—9-CH₃— 332 p-F—Ph— 7-CH₃O— 9-CH₃— 333 p-F—Ph— 7-CH₃— 9-CH₃— 334 p-F—Ph—7-CH₃O— 9-CH₃O— 335 p-F—Ph— 7-(1-pyrrole) 336 p-F—Ph—7-(N)-N′-methylpiperazine 337 p-F—Ph— Ph— 338 p-F—Ph— 7-CH₃C(═CH₂)— 339p-F—Ph— 7-cyclopropyl 340 p-F—Ph— 7-(CH₃)₂NH— 341 p-F—Ph—7-(N)-azetidine 9-CH₃S— 342 p-F—Ph— 7-(N-pyrrolidine) 9-CH₃S— 343p-F—Ph— 7-(CH₃)₂N— 9-CH₃S— 344 m-CH₃O—Ph— 7-(1-pyrazole) 345 m-CH₃O—Ph—7-(N)-N′-methylpiperazine 346 m-CH₃O—Ph— Ph— 347 m-CH₃O—Ph—7-CH₃C(═CH₂)— 348 m-CH₃O—Ph— 7-cyclopropyl 349 m-CH₃O—Ph— 7-(CH₃)₂NH—350 m-CH₃O—Ph— 7-(N)-azetidine 9-CH₃S— 351 m-CH₃O—Ph— 7-(N-pyrrolidine)9-CH₃S— 352 m-CH₃O—Ph— 7-(CH₃)₂N— 9-CH₃S— 353 m-CH₃O—Ph— 6-CH₃O— 7-CH₃O—8-CH₃O— 354 m-CH₃O—Ph— 7-(1-azetidine) 9-CH₃— 355 m-CH₃O—Ph— 7-EtS—9-CH₃— 356 m-CH₃O—Ph— 7-CH₃S(O)— 9-CH₃— 357 m-CH₃O—Ph— 7-CH₃S(O)₂—9-CH₃— 358 m-CH₃O—Ph— 7-PhS— 9-CH₃— 359 m-CH₃O—Ph— 7-CH₃S— 9-CH₃— 360m-CH₃O—Ph— 7-CH₃O— 9-CH₃— 361 m-CH₃O—Ph— 7-CH₃— 9-CH₃— 362 m-CH₃O—Ph—7-CH₃O— 9-CH₃O— 363 thien-2-yl 7-(1-aziridine) 364 thien-2-yl 7-EtS— 365thien-2-yl 7-CH₃S(O)— 366 thien-2-yl 7-CH₃S(O)₂— 367 thien-2-yl 7-PhS—368 thien-2-yl 7-CH₃S— 9-CH₃S— 369 thien-2-yl 7-CH₃O— 9-CH₃O— 370thien-2-yl 7-Et— 371 thien-2-yl 7-iPr— 372 thien-2-yl 7-t-Bu— 373thien-2-yl 7-(1-pyrrole)- 374 thien-2-yl 7-CH₃O— 375 thien-2-yl 7-CH₃S—376 thien-2-yl 7-(1-azetidine) 377 thien-2-yl 7-Me— 378 5-Cl-thien-2-yl7-(1-azetidine) 379 5-Cl-thien-2-yl 7-(1-aziridine) 380 5-Cl-thien-2-yl7-EtS— 381 5-Cl-thien-2-yl 7-CH₃S(O)— 382 5-Cl-thien-2-yl 7-CH₃S(O)₂—383 5-Cl-thien-2-yl 7-PhS— 384 5-Cl-thien-2-yl 7-CH₃S— 9-CH₃S— 3855-Cl-thien-2-yl 7-CH₃O— 9-CH₃O— 386 5-Cl-thien-2-yl 7-Et— 3875-Cl-thien-2-yl 7-iPr— 388 5-Cl-thien-2-yl 7-t-Bu— 389 5-Cl-thien-2-yl7-CH₃O— 390 5-Cl-thien-2-yl 7-CH₃S— 391 5-Cl-thien-2-yl 7-Me— 392thien-2-yl 7-(1-azetidine) 9-CH₃— 393 thien-2-yl 7-EtS—— 9-CH₃— 394thien-2-yl 7-CH₃S(O)— 9-CH₃— 395 thien-2-yl 7-CH₃S(O)₂— 9-CH₃— 396thien-2-yl 7-PhS— 9-CH₃— 397 thien-2-yl 7-CH₃S— 9-CH₃— 398 thien-2-yl7-CH₃O— 9-CH₃— 399 thien-2-yl 7-CH₃— 9-CH₃— 400 thien-2-yl 7-CH₃O—9-CH₃O— 401 thien-2-yl 7-(1-pyrazrole) 402 thien-2-yl7-(N)-N′-methylpiperazine 403 thien-2-yl Ph— 404 thien-2-yl7-CH₃C(═CH₂)— 405 thien-2-yl 7-cyclopropyl 406 thien-2-yl 7-(CH₃)₂NH—407 thien-2-yl 7-(N)-azetidine 9-CH₃S— 408 thien-2-yl 7-(N-pyrrolidine)9-CH₃S— 409 thien-2-yl 7-(CH₃)₂N— 9-CH₃S— 411 5-Cl-thien-2-yl7-(1-pyrazrole) 412 5-Cl-thien-2-yl 7-(N)-N′-methylpiperazine 4135-Cl-thien-2-yl Ph— 414 5-Cl-thien-2-yl 7-CH₃C(═CH₂)— 4155-Cl-thien-2-yl 7-cyclopropyl 416 5-Cl-thien-2-yl 7-(CH₃)₂NH— 4175-Cl-thien-2-yl 7-(N)-azetidine 9-CH₃S— 418 5-Cl-thien-2-yl7-(N-pyrrolidine) 9-CH₃S— 419 5-Cl-thien-2-yl 7-(CH₃)₂N— 9-CH₃S— 4205-Cl-thien-2-yl 7-(1-azetidine) 9-CH₃— 421 5-Cl-thien-2-yl 7-EtS——9-CH₃— 422 5-Cl-thien-2-yl 7-CH₃S(O)— 9-CH₃— 423 5-Cl-thien-2-yl7-CH₃S(O)₂— 9-CH₃— 424 5-Cl-thien-2-yl 7-PhS— 9-CH₃— 425 5-Cl-thien-2-yl7-CH₃S— 9-CH₃— 426 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃— 427 5-Cl-thien-2-yl7-CH₃— 9-CH₃— 428 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃O— 429 thien-2-yl 6-CH₃O—7-CH₃O— 8-CH₃O— 430 5-Cl-thien-2-yl 6-CH₃O— 7-CH₃O— 8-CH₃O—

Examples 232-1394

[0464] Using in each instance a method generally described in those ofExamples 1 to 72 appropriate to the substituents to be introduced,including where necessary other common synthesis expedients well knownto the art, compounds are prepared having the structures set forth inTable 1. The starting materials illustrated in the reaction schemesshown above are varied in accordance with principles of organicsynthesis well known to the art in order to introduce the indicatedsubstituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in theindicated position on the benzo ring (R^(x)).

Example 1395

[0465] Dibutyl 4-fluorobenzene dialdehyde

[0466] Step 1: Preparation of dibutyl 4-fluoro benzene dialdehyde

[0467] To a stirred solution of 17.5 g (123 mmol) of2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambienttemperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). Thedark red solution was stirred at 75 C. for 1.5 hours, or until thestarting material was completely consumed, and then 34 g (135 mmol) ofdibutyl mesylate aldehyde was added at about 50 C. The reaction mixturewas stirred at 75 C. for three hours or until the reaction wascompleted. The cooled solution was poured into water and extracted withethyl acetate. The combined extracts were washed with water severaltimes, dried (MgSO₄) and concentrated in vacuo. Silica gelchromatographic purification of the crude product gave 23.6 g (59%) offluorobenzene dialdehyde as a yellow oil: ¹H NMR (CDCl₃) d 0.87 (t,J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H),7.2-7.35 (m, 1H), 7.5-7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J=2.62 Hz,1H).

[0468] Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol

[0469] To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtainedfrom Step 1 in 650 mL of THF at −60 C. was added 69.8 mL (69.8 mmol) ofDIBAL (1M in THF) via a syringe. The reaction mixture was stirred at −40C. for 20 hours. To the cooled solution at −40 C. was added sufficientamount of ethyl acetae to quench the excess of DIBAL, followed by 3 NHCl. The mixture was extracted with ethyl acetate, washed with water,dried (MgSO₄), and concentrated in vacuo. Silica gel chromatographicpurification of the crude product gave 13.5 g (58%) of recoveredstarting material, and 8.1 g (36%) of the desired fluorobenzyl alcoholas a colorless oil: ¹N (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m,8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1h), 3.03 (s, 2H), 4.79 (s, 2H), 6.96(dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd,J=8.67, 5.64, 1H), 9.40 (s, 1H).

[0470] Step 3: Preparation of dibutyl 4-fluorobenzyl bromide

[0471] To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained fromStep 2 in 100 mL of DMF at −40 C. was added 47 g (50 mmol) ofbromotriphenyphosphonium bromide (Aldrich). The resulting solution wasstirred cold for 30 min, then was allowed to warm to 0 C. To the mixturewas added 10% solution of sodium sulfite and ethyl acetate. The extractwas washed a few times with water, dried (MgSO4), and concentrated invacuo. The mixture was stirred in small amount of ethyl acetate/hexanemixture (1:4 ratio) and filtered through a pad of silica gel, elutingwith same solvent mixture. The combined filtrate was concentrated invacuo to give 9.5 g (98%) of the desired product as a colorless oil: ¹HNMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m,4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15(dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).

[0472] Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide

[0473] To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3in 200 mL of CH₂Cl₂ at 0° C. was added 15.9 g (60 mmol) of mCPBA (64%peracid). The resulting solution was stirred cold for 10 min, then wasallowed to stirred ambient temperature for 5 hours. To the mixture wasadded 10% solution of sodium sulfite and ethyl acetate. The extract waswashed several times with saturated Na₂CO₃, dried (MgSO₄), andconcentrated in vacuo to give 10.2 g (98%) of the desired product as acolorless oil: ¹H NMR (CDCl₃) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m,8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H),7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86,5.64, 1H), 9.49 (s, 1H).

Example 1396

[0474]

[0475] Generic Scheme X: The nucleophilic substitution of anappropriately substituted 2-fluorobenzaldehyde with lithium sulfide orother nucleophilic sulfide anion in polar solvent (such as DMF, DMA,DMSO, etc), followed by the addition of dialkyl mesylate aldehyde (X),provided a dialkyl benzene dialdehyde Y. DIBAL reduction of thedialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z.Conversion of benzyl alcohol to benzyl bromide, followed by oxidation ofsulfide to sulfone yielded the key intermediate W.

[0476] Preparation of N-propylsulfonic Acid

[0477] To a solution of 51 mg (111 μm) Compound X in ethanol (400 μl)was added 1,3 propane sultone (19.5 μl, 222 μm). The reaction wasstirred in a sealed vial at 55° C. for 25 hr. Sample was concentratedunder a nitrogen-stream and purified by reversed phase chromatographyusing acetonitrile/water as eluent (30-45%) and afforded the desiredmaterial as an off-white solid (28.4 mg, 44%): ¹H NMR (CDCL₃) d0.82-0.96 (m, 6H), 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21(m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, 5H),3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, 1H),6.92-7.02 (m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J=8.1Hz, 1H), 8.12-8.25 (m, 1H); MS ES- M−H m/z 579.

Example 1397

[0478] The 7-fluoro, 9-fluoro and 7,9-difluoro analogs or benzothiepinecompounds of this invention can be reacted with sulfur and nitrogennucleophiles to give the corresponding sulfur and nitrogen substitutedanalogs. The following example demonstrates the synthesis of theseanalogs.

[0479]3,3-Dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.

[0480] A mixture of 0.4 g of3,3-dibutyl-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,prepared by previously described method, 0.12 g of sodiummethanethiolate and 20 ml of DMF was stirred at 50 C. for 3 days. Anadditional 0.1 g of sodium methanethiolate was added to the reactionmixture and the mixture was stirred for additional 20 h at 50 C. thenwas concentrated in vacuo. The residue was triturated with water andextracte wiith ether. The ether extract was dried over MgSO₄ andconcentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10%EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5% C.

[0481]3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxideand7,9-Bis(dimethylamino)-3,3-dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.

[0482] A solution of 0.105 g of3,3-dibutyl-7,9-difluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,prepared by the method described previously, in 20 ml of 2 Ndimethylamine in THF was heated at 160 C. in a sealed Parr reactorovernight. The reaction mixture was cooled and concentrated in vacuo.The residue was triturated with 25 ml of water and extracted with ether.The ether extract was dried over MgSO₄ and concentrated in vacuo. Theresdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of anearlier fraction which was identified as3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,MS (CI) m/e 480 (M⁺+1), and 29 mg of a later fraction which wasidentified as7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,MS (CI) m/e 505 (M⁺+1).

[0483] The compounds of this invention can also be synthesized usingcyclic sulfate (A, below) as the reagent as shown in the followingscheme. The following example describes a procedure for using the cyclicsulfate as the reagent.

[0484] Dibutyl cyclic sulfite:

[0485] A solution of 2,2-dibutyl-1,3-propandiol (103 g, 0.548 mol) andtriethylamine (221 g, 2.19 mol) in anhydrous methylene chloride (500 ml)and was stirred at 0 degrees C. under nitrogen. To the mixture, thionylchloride (97.8 g, 0.82 mol) was added dropwise and within 5 min thesolution turned yellow and then turned black when the addition wascompleted within half an hour. The reaction mixture was stirred for 3hrs. GC showed that there was no starting material left. The mixture waswashed with ice water twice then with brine twice. The organic phase wasdried over magnesium sulfate and concentrated under vacuum to give thecyclic sulfite 128 g (100%) as a black oil. Mass spectrum (MS) wasconsistent with the product.

[0486] To a solution of the above compound (127.5 g, 0.54 mol) in 600 mlacetonitrile and 500 ml of water cooled in an ice bath under nitrogenwas added ruthenium (III) chloride (1 g) and sodium periodate (233 g,1.08 mol). The reaction was stirred overnight and the color of thesolution turned black. GC showed that there was no starting materialleft. The mixture was extracted with 300 ml of ether and the etherextract was washed three times with brine. The organic phase was driedover magnesium sulfate and passed through celite. The filtrate wasconcentrated under vacuum and gave the cyclic sulfate 133 g (97.8%) asan oil. Proton, carbon NMR and MS were consistent with the product.

[0487]2-[(2-(4′-Fluorobenzyl)-4-methylphenylthio)methyl]-2-butylhexanol:

[0488] Sodium hydride (60% oil dispersion), 0.27 g (6.68 mmole), waswashed with hexane and the hexane wash was decanted. To the washedsodium hydride was added 20 ml of 2-methoxyethyl ether (diglyme) and themixture was cooled in an ice bath. A solution of 1.55 g (6.68 mmole) of2-(4′-fluorobenzyl)-4-methylbenzenethiol in 10 ml of 2-methoxyethylether was added dropwise to the reaction mixture in 15 min. A mixture of2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of2-methoxyethyl ether was added once and stirred for 30 min at 0 C. thenat room temperature for 1 hr under nitrogen. GC showed that there was nothiol left. The solvent was evaporated and triturated with water thenwas extracted with ether twice. The water layer was separated, treatedwith 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidifiedwith 6N HCl and boiled for 10 min. The reaction mixture was cooled andextracted with ether. The organic layer was washed successively withwater and brine, dried over magnesium sulfate and concentrated undervacuum to give 2.47 g (92.5%) of an oil. Proton NMR, ¹³C NMR and MS wereconsistent with the product.

[0489]2-[(2-(4′-Fluorobenzyl)-4-methylphenylthio)methyl]-2-butylhexanal:

[0490] To a solution of the above product (2 g, 4.9 mmol) in 40 mlmethylene chloride cooled in an ice bath under nitrogen was addedpyridinium chlorochromate (2.18 g, 9.9 mmol) at once. The reaction wasstirred with 3 hrs and filtered through a bed of silica gel. Thefiltrate was concentrated under vacuum, to give 1.39 g (70%) of an oil.Proton, carbon NMR and MS were consistent with the product.

[0491]2-[(2-(4′-Fluorobenzyl)-4-methylphenylsulfonyl)methyl]-2-butylhexanal

[0492] To a solution of the above product (0.44 g, 1.1 mmole) in 20 mlmethylene chloride solution cooled in an ice bath under nitrogen wasadded 70% m-chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. Thereaction mixture was stirred for 18 hrs and filtered. The filtrate waswashed successively with 10% NaOH (3×), water and brine,,dried overmagnesium sulfate and concentrated under vacuum to give 0.42 g (90%) ofan oil. Proton, carbon NMR and MS were consistent with the product.

[0493]3,3-Dibutyl-7-methyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide:

[0494] A mixture of 0.37 g (0.85 mmol) of the above product in 30 ml ofanhydrous THF was stirred at 0% C. Then potassium t-butoxide (102 mg,0.85 mmol) was added. After 3 hrs, TLC showed that there was a productand some starting material left. The crude reaction mixture wasacidified with 10% HCl and extracted with ether. The ether extract waswashed successively with water and brine, dried with MgSO₄ andconcentrated under vacuum. The residue was purified by HPLC (10%EtOAc-Hexane). The first fraction was 0.1 g of starting material as anoil and the second fraction was a white solid, 0.27 g (75%). Proton NMRand carbon N were consistent with the desired product. Mass spectrum(CI) also confirmed the product, m/e 433 (M⁺ 1).

Example 1398

[0495]

[0496] In an inert atmosphere, weigh out 68.3 gms phosphoruspentachloride (0.328 mole Aldrich 15,777-5) into a 2-necked 500 ml roundbottom flask. Fit flask with a N₂ inlet adapter and suba seal. Removefrom inert atmosphere and begin N₂ purge. Add 50 mls anhydrouschlorobenzene (Aldrich 28,451-3) to the PCl₅ via syringe and beginstirring with magnetic stir bar.

[0497] Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich12,511-3). Slowly add to the chlorobenzene solution while under N₂purge. Stir at room temperature overnight. After stirring at roomtemperature for ˜20 hrs, place in oil bath and heat at 50C for 1 hr.Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane.Dry acid chloride wt=61.95 gms. Store in inert and dry atmosphere.

[0498] In inert atmosphere, dissolve acid chloride with 105 mlsanhydrous anisole (0.97 mole Aldrich 29,629-5). Place solution in a2-necked 500 ml round bottom flask.

[0499] Weigh out 45.1 gms aluminum chloride (0.34 moles Aldrich29,471-3) and place in a solid addition funnel. Fit reaction flask withaddition funnel and a N₂ inlet adapter. Remove from inert atmosphere.Chill reaction solution with ice bath and begin N₂ purge. Slowly addAlCl₃ to chilled solution. After addition is complete, allow to warm toroom temperature. Stir overnight

[0500] Quench reaction by pouring into a solution of 300 mls 1N HCl andice. Stir 15 min. Extract twice with ether. Combine organic layers andextract twice with 2% NaOH, then twice with deionized H₂O. Dry withMgSO₄, filter and rotovap to dryness. Remove anisole by high vacuum.Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuumline. Wt=35.2 gms. Yield 41%. Obtain NMR and mass spec (m/z=292).

[0501] Dissolve 38.10 gms (0.131 moles) of the benzophenone from step 1in 250 mls anhydrous methylene chloride. Place in a 3 liter flask fittedwith N₂ inlet, addition funnel and stopper. Stir with magnetic stir bar.Chill solution with ice bath.

[0502] Prepare a solution of 39.32 gms trifluoromethane sulfonic acid(0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride.Place in addition funnel and add dropwise to chilled solution under N₂.Stir 5 minutes after addition is complete.

[0503] Prepare a solution of 22.85 gms triethyl silane (0.197 moleAldrich 23,019-7) and 170 mls anhydrous methylene chloride. Place inaddition funnel and add dropwise to chilled solution under N₂. Stir 5minutes after addition is complete.

[0504] Prepare a second solution of 39.32 gms trifluoromethane sulfonicacid and 170 mls anhydrous methylene chloride. Place in addition funneland add dropwise to chilled solution under N₂. Stir 5 minutes afteraddition is complete.

[0505] Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and adddropwise to chilled solution under N₂. After all additions are madeallow to slowly warm to room temperature overnight. Stir under N₂overnight.

[0506] Prepare 1300 mls saturated NaHCO₃ in a 4 liter beaker. Chill withice bath. While stirring vigorously, slowly add reaction mixture. Stirat chilled temperature for 30 min. Pour into a separatory funnel andallow separation. Remove organic layer and extract aqueous layer 2 timeswith methylene chloride. Dry organic layers with MgSO₄. Crystallize fromethanol. Dry on vacuum line. Dry wt=28.8 gms. Confirm by NMR and massspec (m/z=278).

[0507] Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mlsanhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stirbar. Fit flask with water condenser, N₂ inlet, and stopper. Add 1.84 gmsLi₂S (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at75° C. under N₂ overnight then cool to room temperature.

[0508] Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve withanhydrous DMSO and add to reaction solution. Purge well with N₂, heatovernight at 80° C.

[0509] Cool to room temperature. Prepare 500 mls of 5% acetic acid in a2 liter beaker. While stirring, slowly add reaction mixture. Stir 30min. Extract with ether 3 times. Combine organic layers and extract withwater and sat'd NaCl. Dry organic layer with MgSO₄, filter and rotovapto dryness. Dry oil on vacuum line. Obtain pure product by columnchromatography using 95% hexane and 5% ethyl acetate as the mobilephase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).

[0510] Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mlsanhydrous methylene chloride. Place in a 250 ml round bottom flask withmagnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solutionwith ice bath under N₂ purge. Slowly add 11.54 gms 3-chloroperbenzoicacid (0.0435 moles, Fluka 25800, ˜65%). After addition is complete warmto room temperature and monitor reaction by TLC. Reaction goes quicklyto the sulphoxide intermediate but takes 8 hrs to convert to thesulphone. Chill solution over night in freezer. Filter solid fromreaction, extract filtrate with 10% K₂CO₃. Extract aqueous layer twicewith methylene choride. Combine organic layers and dry with MgSO₄.Filter and rotovap to dryness. Obtain pure product by crystallizing fromethanol or isolating by column chromatography. Obtain NMR and mass spec(m/z=476).

[0511] Reaction is done in a 300 ml stainless steel Parr stirred minireactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add160 mls ethanol. For safety reasons next two compounds are added in a N₂atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204moles, Aldrich 25,254-9, about 37 wt % in water) and 1.45 gms 10%Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glovebag. Purge reactor three times with H₂. Heat to 55° C. under H₂. Runreaction at 200 psig H₂, 55° C., and a stir rate of 250 rpm. Runovernight under these conditions.

[0512] Cool reactor and vent H₂. Purge with N₂. Check progress of run byTLC. Reaction is a mixture of desired product and intermediate. Filterreaction mixture over a bed of celite washing well with ether. Rotovapand redissolve with ether. Extract with water. Dry organic layer withMgSO₄, filter and rotovap to dryness. Dry on vacuum line.

[0513] Charge reactor again with same amounts, seal reactor and runovernight under same conditions. After second run all of the materialhas been converted to the desired product. Cool and vent H₂ pressure.Purge with N₂. Filter over a bed of celite, washing well with ether.Rotovap to dryness. Dissolve with ether and extract with water. Dryorganic layer with MgSO₄, filter and rotovap to dryness. Dry on vacuumline. Obtain NMR and mass spec (m/z=474).

[0514] Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mlsanhydrous THF. Place in a 250 ml round bottom flask with magnetic stirbar. Fit flask with N₂ inlet and stopper. Chill solution with ice/saltbath under N₂ purge. Slowly add 2.55 gms potassium t-butoxide (0.227mole Aldrich 15,667-1). After addition is complete, continue to stir at−10° C. monitoring by TLC. Once reaction is complete, quench by adding135 mls 10% HCl stirring 10 min. Extract three times with ether. Dryorganic layer with MgSO₄, filter and rotovap to dryness. Crystallizefrom ether. Obtain NMR and mass spec (m/z=474).

[0515] Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mlsanhydrous chloroform. Place in a 250 ml round bottom flask with magneticstir bar. Fit flask with N₂ inlet adapter and suba seal. Chill solutionwith dry ice/acetone bath under a N₂ purge. Slowly add, via syringe,2.84 mls boron tribromide (0.03 moles Aldrich 20,220-7). Stir at coldtemperature for 15 min after addition then allow to warm to roomtemperature. Monitor reaction progress by TLC. Reaction is usuallycomplete in 3 hrs.

[0516] Chill solution with ice bath. Quench with 100 mls 10% K₂CO₃ whilestirring rapidly. Stir 10 min. then transfer to sep funnel and allowseparation. Remove aqueous layer. Extract organic layer once with 10%HCl, once H₂O, and once with saturated NaCl solution. Dry organic layerwith MgSO₄, filter and rotovap to dryness. Crystallize product fromether. Obtain NMR and mass spec (m/z=460).

[0517] Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. inmineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fitflask with N₂ inlet and stopper. Chill NaH with ice bath and begin N₂purge.

[0518] Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrousDMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33gms K₂CO₃ (9.57 mmoles Fisher P-208).

[0519] Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmolesAldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reactionmixture. Warm to room temperature then heat to 40° C. overnight underN₂.

[0520] Cleanup by diluting with ether and extracting sequentially with5% NaOH, H₂O, and saturated NaCl. Dry organic layer with MgSO₄, filterand dry. Obtain pure product by column chromatography using 75% hexane25% ethyl acetate as the mobile phase. Obtain NMR and mass spec(m/z=702).

[0521] Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrousacetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vesselwith magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich23,962-3) dissolved in 10 mls anhydrous acetonitrile. Purge well with N₂then close system. Heat at 45° C. Monitor reaction by TLC. Reaction isusually complete in 48 hrs.

[0522] Perform cleanup by removing acetonitrile under vacuum. Redissolvewith anhydrous chloroform and precipitate quaternary ammonium salt withether. Repeat several times. Dry to obtain crystalline product. ObtainNMR and mass spec (m/z=675).

Example 1399

[0523]

[0524] To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO wasadded 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via additionfunnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) viaaddition funnel. Stirred at ambient temperature for fifteen minutes.Poured reaction contents into 1.0 L of water and extracted three timeswith ethyl acetate. The organic layer was dried over MgSO₄ andconcentrated in vacuo. Purified by silica-gel chromatography through a200 mL plug using hexanes (100%) as elutant yielded 103.2 g (80%) of 1as a clear colorless liquid. ¹H NMR (CDCl₃) d 3.39 (s, 3H), 4.42 (s,2H), 7.18-7.27 (m, 2H), 7.12 (d, J=7.45, 1H), 7.50 (s, 1H).

[0525] To a cooled (−78° C.) solution of 95 g (472 mmol) of 1 in 1.5 LTHF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixturewas stirred for one hour, and then to it was added 180 g of zinc iodide(566 mmol) dissolved in 500 ml THF. The mixture was stirred thirtyminutes, allowed to warm to 5 C., cooled to −10° C. and to it was added6 g of Pd(PPh₃)₄ (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708mmol). The mixture was stirred at ambient temperature for 18 hoursandthen cooled to 10° C., quenched with water, partitioned between ethylacetate and water, and washed organic layer with 1N HCL and with 1NNaOH. The organic layer was dried over MgSO₄ and concentrated in vacuo.Purification by silica gel chromatography (Waters Prep-500) using 5%ethyl acetate/hexanes as elutant gave 53.6 g (43%) of 2 as an orangeoil. ¹H NMR (CDCl₃) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H),7.47 (t, J=7.50, 1H), 7.57 (d, J=7.45, 1H), 7.73 (d, J=7.45, 1H), 7.80(s, 1H).

[0526] A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol)in 250 mL DMF was heated to 100° C. for 18 hours. The reaction wascooled (0° C.) and 60.7 g of X (the cyclic sulfate compound of example1397) (242.8 mmol) in 50 mL DMF was added. Stirred at ambienttemperature for 18 hours then condensed in vacuo. Added 1 L water toorganic residue and extracted twice with diethyl ether. Aqueous layeracidified (pH 1) and refluxed 2 days. Cooled to ambient temperature andextracted with methylene chloride, dried organic layer over MgSO₄ andcondensed in vacuo. Purification by silica gel chromatography (WatersPrep-500) using 10% ethyl acetate/hexanes as elutant gave 42.9 g (48%)of 3 as a yellow oil. ¹H NMR (CDCl₃) d 0.86 (t, J=7.25 Hz, 6H),1.10-1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s,3H), 7.02 (dd, J=8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J=8.19 Hz and 2.82Hz, 1H), 7.45 (t, J=7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J=7.85 Hz,1H), 7.74 (s, 1H),

[0527] To a cooled (−40° C.) solution of 42.9 g (96.2 mmol) of 3 in 200mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid(12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane(30.7 mL, 192.4 mmol). Stirred at −20° C. for two hours, quenched withwater and warmed to ambient temperature. Partitioned between methylenechloride and water, dried the organic layer over MgSO₄ and condensed invacuo. Purification by silica gel chromatography (Waters Prep-500) using10% ethyl acetate/hexanes as elutant gave 24.2 g (60%) of 4 as a oil. ¹HNMR (CDCl₃) d 0.89 (t, J=7.05 Hz, 6H), 1.17-1.40 (m, 12H), 1.46 (t,J=5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J=5.23 Hz, 2H),4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J=9.67 Hz, 1H), 6.90 (t, J=8.46 Hz,1H), 7.09 (d, J=7.45 Hz, 1H), 7.15-7.21 (m, 2H), 7.25-7.32 (m, 2H), 7.42(m, 1H).

[0528] To a cooled (15-18° C.) solution of 24.2 g (55.8 mmol) of 4 in100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195mmol). Stirred at ambient temperature for thirty minutes. Poured intocold water and extracted three times with ethyl acetate. Washed organicswith 5% HCl (300 mL) and then with brine (300 mL), dired organics overMgSO₄ and condensed in vacuo to give 23.1 g (96%) of 5 as a light brownoil. ¹H NMR (CDCl₃) d 0.87 (t, J=7.05 Hz, 6H), 1.01-1.32 (m, 8H),1.53-1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s,2H), 6.81 (dd, J=9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J=8.62 Hz, 1H), 7.07(d, J=7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J=7.65 Hz, 1H), 7.26-7.32 (m,1H), 7.42 (dd, J=8.66 Hz and 5.64 Hz, 1H), 9.40 (s, 1H).

[0529] To a cooled (0° C.) solution of 23.1 g (53.6 mmol) of 5 in 200 mLmethylene chloride was added 28.6 g meta cholorperoxy-benzoic acid(112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with100 mL 10% Na₂SO₃, partitioned between water and methylene chloride.Dried organic layer over MgSO₄ and condensed in vacuo to give 24.5 g(98%) of 6 as a light yellow oil. ¹H NMR (CDCl₃) d 0.86-1.29 (m, 14H),1.58-1.63 (m, 2H), 1.82-1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H), 4.44(s, 2H), 4.50 (s, 2H), 6.93 (d, J=9.07 Hz, 1H), 7.10-7.33 (m, 5H), 8.05(s, 1H), 9.38 (s, 1H).

[0530] To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THFcontained in a stainless steel reaction vessel was added 100 mL of a 2.0M solution of dimethyl amine and 20 mL of neat dimethyl amine. Thevessel was sealed and heated to 110° C. for 16 hours. The reactionvessel was cooled to ambient temperature and the contents concentratedin vacuo. Purification by silica gel chromatography (Waters prep-500)using 15% ethyl acetate/hexanes gave 21.8 g (84%) of 7 as a clearcolorless oil. ¹H NMR (CDCl₃) d 0.85 (t, J=7.25 Hz, 6H), 0.93-1.29 (m,8H), 1.49-1.59 (m, 2H), 1.70-1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H),4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J=9.0 Hz and 2.61Hz, 1H), 7.13 (d, J=7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J=7.85 Hz, 1H),7.82 (d, J=9.06 Hz, 1H), 9.36 (s, 1H).

[0531] A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooledto 0° C. 58.2 mL of a 1 M solution of potassium t-butoxide was addedslowly, maintaining the temperature at <5° C. Stirred for 30 minutes,then quenched with 50 mL of saturated ammonium chloride. The organiclayer was partitioned between ethyl acetate and water, dried over MgSO4and concentrated in vacuo. Purification by recrystalization from ˜10%ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The motherliquor was purified by silica gel chromatography (Waters Prep-500) using30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a whitesolid. MS (FABLi⁺) m/e 494.6. HRMS (EI⁺) calculated for M+H 487.2756.Found 487.2746.

[0532] A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylenechloride was cooled to −60° C. 4.1 mL of a 1M solution of borontribromide was added. Stirred at ambient temperature for thirty minutes.Cooled reaction to −10° C. and quenched with 50 mL of water. The organiclayer was partitioned between methylene chloride and water, dried overMgSO₄ and concentrated in vacuo. Purification by recrystalization from50% ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a whitesolid. MS (FABH⁺) m/e 537. HEMS (FAB) calculated for M 536.1834. Found536.1822.

[0533] A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) ofpyridine in 30 mL of acetonitrile was stirred at ambient temperature for18 hours. The reaction was concentrated in vacuo. Purification byrecrystallization from methanol/diethyl ether gave 1.19 g (96%) of 10 asan off white solid. MS (FAB⁺) m/e 535.5.

Example 1398

[0534]

[0535] To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde ofExample 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol wasadded 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis(triphenylphoshine) palladium (0) (0.7 mmol) and 45 mL of a 2 M solutionof sodium carbonate in water. This heterogeneous mixture was refluxedfor three hours, then cooled to ambient temperature and partitionedbetween ethyl acetate and water. The organic layer was dried over MgSO₄and concentrated in vacuo. Purification by silica gel chromatography(Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%)of the title compound as a yellow solid. ¹H NMR (CDCl₃) d 0.88 (t,J=7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H),3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J=10.5 and 2.4 Hz, 1H), 7.15 (dt,J =8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05-8.16 (m, 3H), 9.40 (s,1H).

[0536] A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to0° C. in an ice bath. 20 mL of a 1 M solution of potassium t-butoxidewas added slowly, maintaining the temperature at <5° C. Stirring wascontinued for 30 minutes, then the reaction was quenched with 100 mL ofsaturated ammonium chloride. The mixture was partitioned between ethylacetate and water; the organic layer was washed with brine, then dried(MgSO₄) and concentrated in vacuo. Purification by silica gelchromatography through a 100 ml plug using CH₂Cl₂ as eluent yielded 4.3g (90%) of 3 as a pale yellow foam. ¹H NMR (CDCl₃) d 0.93 (t, J=7.25 Hz,6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16(q_(AB), J_(AB)=15.0 Hz, ΔV=33.2 Hz, 2H), 4.17 (d, J=6.0 Hz, 1H), 5.67(s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J=8.5 and 2.9 Hz,1H), 7.64 (t, J=8.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 8.13 (dd, J=9.9 and3.6 Hz, 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H). MS(FABH⁺) m/e (relativeintensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907.Found 464.1905.

[0537] To a cooled (0° C.) solution of 4.3 g (9.3 mmol) of 3 in 30 mlTHF contained in a stainless steel reaction vessel was added 8.2 gdimethyl amine (182 mmol). The vessel was sealed and heated to 110° C.for 16 hours. The reaction vessel was cooled to ambient temperature andthe contents concentrated in vacuo. Purification by silica gelchromatography (Waters Prep-2000) using an ethyl acetate/hexanesgradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid.¹H NMR (CDCl₃) d 0.80-0.95 (m, 6H), 0.996-1.53 (m, 8H) 1.60-1.69 (m,3H), 2.11-2.28 (m, 1H), 2.79 (s, 6H), 3.09 (q_(AB), J_(AB)=15.0 Hz,DV=45.6 Hz, 2H), 4.90 (d, J=9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J=2.1Hz, 1H), 6.52 (dd, J=9.6 and 2.7 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.85(d, J=7.80 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 8.20 (dd, J=8.4 and 1.2 Hz,1H), 8.43 (s, 1H). MS(FABH⁺) m/e (relative intensity) 489.6 (100), 471.5(25). HRMS calculated for M+H 489.2423. Found 489.2456.

[0538] To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in astainless steel Parr reactor was added 1 g 10% palladium on carbon. Thereaction vessel was sealed, purged twice with H₂, then charged with H₂(100 psi) and heated to 45° C. for six hours. The reaction vessel wascooled to ambient temperature and the contents filtered to remove thecatalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of5. ¹H NMR (CDCl₃) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m,1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (q_(AB), J_(AB)=15.1 Hz,DV=44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d,J=2.4 Hz, 1H), 6.52 (dd, J=12.2 and 2.6 Hz, 1H), 6.65 (dd, J=7.8 and 1.8Hz, 1H), 6.83 (s, 1H), 6.93 (d, J=7.50 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H),7.89 (d, J=8.9 Hz, 1H). MS(FABH⁺) m/e (relative intensity) 459.7 (100).HRMS calculated for M+H 459.2681. Found 459.2670.

[0539] Step 6. Preparation of 6

[0540] To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6mmol) TEA. The reaction was stirred 10 minutes, then partitioned betweenethyl acetate and brine. The organic layer was dried (MgSO₄) andconcentrated in vacuo. Purification by silica gel chromatography througha 70 ml MPLC column using a gradient of ethyl acetate (20-50%) in hexaneas eluent yielded 0.9 g (73%) of 6 as a pale yellow oil. ¹H NMR (CDCl₃)d 0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2.00(m, 4H), 2.12-2.26 (m, 4H) 2.38 (t, J=6.9 Hz, 2H), 2.80 (s, 6H), 3.07(q_(AB), J_(AB)=15.6 Hz, DV=40.4 Hz, 2H), 3.43 (t, J=6.9 Hz, 2H), 4.10(s, 1H), 5.51 (s, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.3 and 2.7Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78 (d, J=8.1 Hz, 1H), 7.90(d, J=9.0 Hz, 1H).

[0541] To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add18 g (178 mmol) TEA. Heat at 55° C. for 16 hours. The reaction mixturewas cooled to ambient temperature and concentrated in vacuo.Purification by reverse-phase silica gel chromatography (Waters DeltaPrep 3000) using an acetonitrile/water gradient containing 0.05% TFA(20-65% acetonitrile) gave 0.8 g (73%) of 7 as a white foam. ¹H NMR(CDCl₃) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H),2.09-2.24 (m, 1H), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q_(AB),J_(AB)=15.6 Hz, DV=18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44(s, 1H), 6.08 (d, J=1.8 Hz, 1H), 6.57 (dd, J=9.3 and 2.7 Hz, 1H), 7.24(t, J=7.5 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.74(s, 1H), 7.88 (d, J=9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304;observed 642.4343.

Example 1400

[0542]

[0543] A 12-liter, 4-neck round-bottom flask was equipped with refluxcondenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel.The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. Asolution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) wasadded via addition funnel over a period of 2.5 h. The reaction mixturewas heated to reflux (100 C.) for 1 h. A solution of 3-methoxybenzylchloride (783.0 g/5.000 mol) in toluene (750 mL) was added via additionfunnel while maintaining reflux. After 15 h. refluxing, the mixture wascooled to room temperature and poured into H₂O (2.5 L). After 20 min.stirring, the layers were separated, and the organic layer was extractedwith a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOHlayer was added to 20% aqueous potassium hydroxide, and the mixture wasstirred for 30 min. The mixture was then washed 5 times with toluene.The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOHsolutions were combined and acidified with concentrated HCl. The acidicsolution was extracted three times with ethyl ether, dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified byKugelrohr distillation to give a clear, colorless oil (449.0 g/39%yield). b.p.: 120-130 C./50 mtorrHg. ¹H NMR and MS [(M+H)⁺=233]confirmed desired structure.

[0544] A 12-liter, 3-neck round-bottom flask was fitted with mechanicalstirrer and N₂ gas adaptor. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) anddimethylformamide were added. The solution was cooled to 6 C., andsodium hydride (55.5 g/2.197 mol) was added slowly. After warming toroom temperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) wasadded. After 15 h, the reaction mixture was poured into H₂O (4.0 L), andextracted two times with ethyl ether. The combined organic layers werewashed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, andconcentrated in vacuo to give the product (605.3 g, 97% yield). ¹H NMRand MS [(M+H)⁺=320] confirm desired structure.

[0545] A 12-liter, round-bottom flask was equipped with N₂ gas adaptor,mechanical stirrer, and reflux condenser. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895mol) and phenyl ether (2.0 kg) were added, and the solution was heatedto reflux for 2 h. The mixture was stirred for 64 h. at room temparatureand then heated to reflux for 2 h. After cooling to room temperature,MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirredfor 15 h. potassium hydroxide (425.9 g/7.590 mol) was added, and themixture was heated to reflux for 4 h. After cooling to room temparature,the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0L), and extracted with H₂O. The aqueous extracts were combined,acidified with concentrated HCl, and extracted with ethyl ether. Theether extracts were dried (MgSO₄), filtered, and concentrated in vacuoto give an amber oil (463.0 g, 98% yield). ¹H NMR confirmed desiredstructure.

[0546] A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2 mmol) and2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixturewas allowed to warm to room temperature, 2,2-Dibutylpropylene sulfate(110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h.The reaction mixture was concentrated by rotavap and dissolved in H₂O.The aqueous solution was washed with ethyl ether, and concentrated H₂SO₄was added. The aqueous solution was heated to reflux for 30 min, cooledto room temperature, and extracted with ethyl ether. The ether solutionwas dried (MgSO₄), filtered, and conc'd in vacuo to give an amber oil(143.94 g/85% yield). ¹H NMR and MS [(M+H)⁺419] confirm the desiredstructure.

[0547] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, and mechanical stirrer. The system was purged with N₂. Thecorresponding alcohol (143.94 g/343.8 mmol) and CH₂Cl₂ (1.0 L) wereadded and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol)was added. After 6 h., CH₂Cl₂ was added. After 20 min, the mixture wasfiltered through silica gel, washing with CH₂Cl₂. The filtrate wasconcentrated in vacuo to give a dark yellow-red oil (110.6 g, 77%yield). ¹H NMR and MS [(M+H)⁺=417] confirm the desired structure.

[0548] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂. Thecorresponding sulfide (110.6 g/265.5 mmol) and CH₂Cl₂ (1.0 L) wereadded. The solution was cooled to 0 C., and 3-chloroperbenzoic acid(158.21 g/531.7 mmol) was added portionwise. After 30 min, the reactionmixture was allowed to warm to room temperature After 3.5 h, thereaction mixture was cooled to 0 C. and filtered through a fine frittedfunnel. The filtrate was washed with 10% aqueous K₂CO₃. An emulsionformed which was extracted with ethyl ether. The organic layers werecombined, dried (MgSO₄), filtered, and concentrated in vacuo to give theproduct (93.2 g, 78% yield). ¹H NMR confirmed the desired structure.

[0549] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, mechanical stirrer, and a powder addition funnel. The systemwas purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF(1.0 L) were added, and the mixture was cooled to 0 C. Potassiumtert-butoxide (23.35 g/208.1 mmol) was added via addition funnel. After1 h, 10% aq/HCl (1.0 L) was added. After 1 h, the mixture was extractedthree times with ethyl ether, dried (MgSO₄), filtered, and concentratedin vacuo. The crude product was purified by recryst. from 80/20hexane/ethyl acetate to give a white solid (32.18 g). The mother liquorwas concentrated in vacuo and recrystallized from 95/5 toluene/ethylacetate to give a white solid (33.60 g/combined yield: 71%). ¹H NMRconfirmed the desired product.

[0550] A Fisher porter bottle was fitted with N₂ line and magneticstirrer. The system was purged with N₂. The correspondingfluoro-compound (28.1 g/62.6 mmol) was added, and the vessel was sealedand cooled to −78 C. Dimethylamine (17.1 g/379 mmol) was condensed via aCO₂/acetone bath and added to the reaction vessel. The mixture wasallowed to warm to room temperature and was heated to 60 C. After 20 h,the reaction mixture was allowed to cool and was dissolved in ethylether. The ether solution was washed with H₂O, saturated aqueous NaCl,dried (MgSO₄), filtered, and concentrated in vacuo to give a white solid(28.5 g/96% yield). ¹H NMR confirmed the desired structure.

[0551] A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and magnetic stirrer. The system was purged with N₂. Thecorresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL)were added. The reaction mixture was cooled to −78 C., and borontribromide (10.50 g/41.9 mmol) was added. The mixture was allowed towarm to room temperature After 4 h, the reaction mixture was cooled to 0C. and was quenched with 10% K₂CO₃ (100 mL). After 10 min, the layerswere separated, and the aqueous layer was extracted two times with ethylether. The CHCl₃ and ether extracts were combined, washed with saturatedaqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to givethe product (6.27 g/98% yield). ¹H NMR confirmed the desired structure.

[0552] In a 250 ml single neck round bottom Flask with stir bar place 2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) Aldrich D8,720-1 (2.4 mmol, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH(aqueous).Stir 15 minutes and then separate by ether extraction and dry overanhydrous potassium carbonate.

[0553] In a separate 2-necked 250 ml round bottom flask with stir baradd sodium hydride (60% dispersion in mineral oil, 100 mg, 2.6 mmol) and34 ml of DMF. Cool to ice temperature. Next add phenol product (previousstep) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution preparedabove. Heat to 40 C. for 3 days. The product which contained no startingmaterial by TLC was diluted with ether and extracted with 1 portion of5% NaOH, followed by water and then brine. The ether layer was driedover magnesium sulfate and isolated by removing ether by rotaryevaporation (1.3 gms). The product may be further purified bychromatography (SiO2 99% ethyl acetate/1% NH4OH at 5 ml/min.). Isolatedyield: 0.78 g (mass spec, and H1 NMR)

[0554] The product from step 10 (0.57 gms, 1.02 millimole fw 558.83g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 mlacetonitrile in a fischer-porter bottle and heated to 45 C. for 3 days.The solution was evaporated to dryness and redissolved in 5 mls ofchloroform. Next ether was added to the chloroform solution and theresulting mixture was chilled. The desired product is isolated as aprecipitate 0.7272 gms. Mass spec M−I=587.9, H NMR).

Example 1401

[0555]

[0556] A 12-liter, 4-neck round-bottom flask was equipped with refluxcondenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel.The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. Asolution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) wasadded via addition funnel over a period of 2.5 h. The reaction mixturewas heated to reflux (100 C.) for 1 h. A solution of 3-methoxybenzylchloride (783.0 g/5.000 mol) in toluene (750 mL) was added via additionfunnel while maintaining reflux. After 15 h. refluxing, the mixture wascooled to room temperature and poured into H₂O (2.5 L). After 20 min.stirring, the layers were separated, and the organic layer was extractedwith a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOHlayer was added to 20% aqueous potassium hydroxide, and the mixture wasstirred for 30 min. The mixture was then washed 5 times with toluene.The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOHsolutions were combined and acidified with concentrated HCl. The acidicsolution was extracted three times with ethyl ether, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified byKugelrohr distillation to give a clear, colorless oil (449.0 g/39%yield). b.p.: 120-130 C./50 mtorrHg. ¹H NMR and MS [(M+H)⁺=233]confirmed desired structure.

[0557] A 12-liter, 3-neck round-bottom flask was fitted with mechanicalstirrer and N₂ gas adaptor. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) anddimethylformamide were added. The solution was cooled to 6 C., andsodium hydride (55.5 g/2.197 mol) was added slowly. After warming toroom temperature dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) wasadded. After 15 h, the reaction mixture was poured into H₂O (4.0 L), andextracted two times with ethyl ether. The combined organic layers werewashed with H₂O and saturated aqueous NaCl, dried over MgSO₄, filtered,and concentrated in vacuo to give the product (605.3 g, 97% yield). ¹HNMR and MS [(M+H)⁺=320] confirm desired structure.

[0558] A 12-liter, round-bottom flask was equipped with N₂ gas adaptor,mechanical stirrer, and reflux condenser. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895mol) and phenyl ether (2.0 kg) were added, and the solution was heatedto reflux for 2 h. The mixture was stirred for 64 h. at room temperatureand then heated to reflux for 2 h. After cooling to room temperature,MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirredfor 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and themixture was heated to reflux for 4 h. After cooling to room temperature,the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0L), and extracted with H₂O. The aqueous extracts were combined,acidified with conc. HCl, and extracted with ethyl ether. The etherextracts were dried (MgSO₄), filtered, and concentrated in vacuo to givean amber oil (463.0 g, 98% yield). ¹H NMR confirmed desired structure.

[0559] A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2 mmol) and2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixturewas allowed to warm to room temperature 2,2-Dibutylpropylene sulfate(110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h.The reaction mixture was concentrated by rotavap and dissolved in H₂O.The aqueous solution was wasted with ethyl ether, and conc. H₂SO₄ wasadded. The aqueous solution was heated to reflux for 30 min, cooled toroom temperature, and extracted with ethyl ether. The ether solution wasdried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil(143.94 g/85% yield). ¹H NMR and MS [(M+H)⁺=419] confirm the desiredstructure.

[0560] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, and mechanical stirrer. The system was purged with N₂. Thecorresponding alcohol (143.94 g/343.8 mmol) and CH₂Cl₂ (1.0 L) wereadded and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol)was added. After 6 h., CH₂Cl₂ was added. After 20 min, the mixture wasfiltered through silica gel, washing with CH₂Cl₂. The filtrate wasconcentrated in vacuo to give a dark yellow-red oil (110.6 g, 77%yield). ¹H NMR and MS [(M+H)⁺=417] confirm the desired structure.

[0561] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂. Thecorresponding sulfide (110.6 g/265.5 mmol) and CH₂Cl₂ (1.0 L) wereadded. The solution was cooled to 0 C., and 3-chloroperbenzoic acid(158.21 g/531.7 mmol) was added portionwise. After 30 min, the reactionmixture was allowed to warm to room temperature After 3.5 h, thereaction mixture was cooled to 0 C. and filtered through a fine frittedfunnel. The filtrate was washed with 10% aqueous K₂CO₃. An emulsionformed which was extracted with ethyl ether. The organic layers werecombined, dried (MgSO₄), filtered, and concentrated in vacuo to give theproduct (93.2 g, 78% yield). ¹H NMR confirmed the desired structure.

[0562] A 2-liter, 4-neck, round-bottom, flask was equipped with N₂ gasadaptor, mechanical stirrer, and a powder addition funnel. The systemwas purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF(1.0 L) were added, and the mixture was cooled to 0 C. Potassiumtert-butoxide (23.35 g/208 mmol) was added via addition funnel. After 1h, 10% aq/HCl (1.0 L) was added. After 1 h, the mixture was extractedthree times with ethyl ether, dried (MgSO₄), filtered, and concentratedin vacuo. The crude product was purified by recrystallized from 80/20hexane/ethyl acetate to give a white solid (32.18 g). The mother liquorwas concentrated in vacuo and recrystallized from 95/5 toluene/ethylacetate to give a white solid (33.60 g, combined yield: 71%). ¹H NMRconfirmed the desired product.

[0563] A Fisher porter bottle was fitted with N₂ line and magneticstirrer. The system was purged with N₂. The correspondingfluoro-compound (28.1 g/62.6 mmol) was added, and the vessel was sealedand cooled to −78 C. Dimethylamine (17.1 g/379 mmol) was condensed via aCO₂/acetone bath and added to the reaction vessel. The mixture wasallowed to warm to room temperature and was heated to 60 C. After 20 h,the reaction mixture was allowed to cool and was dissolved in ethylether. The ether solution was washed with H₂O, saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated in vacuo to give a whitesolid (28.5 g/96% yield). ¹H NMR confirmed the desired structure.

[0564] A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and magnetic stirrer. The system was purged with N₂. Thecorresponding methoxy-compound (6.62 g/14.00 mmol) and CHCl₃ (150 mL)were added. The reaction mixture was cooled to −78 C., and borontribromide (10.50 g/41.9 mmol) was added. The mixture was allowed towarm to room temperature After 4 h, the reaction mixture was cooled to 0C. and was quenched with 10% K₂CO₃ (100 mL). After 10 min, the layerswere separated, and the aqueous layer was extracted two times with ethylether. The CHCl₃ and ether extracts were combined, washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo togive the product (6.27 g/98% yield). ¹H NMR confirmed the desiredstructure.

[0565] In a 250 ml single neck round bottom flask with stir bar place2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) AldrichD8, 720-1 (2.4 millimoles, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dryover anhydrous potassium carbonate.

[0566] In a separate 2-necked 250 ml round bottom flask with stir baradd sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol)and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solutionprepared above. Heat to 40 C. for 3 days. The product which contained nostarting material by TLC was diluted with ether and extracted with 1portion of 5% NaOH, followed by water and then brine. The ether layerwas dried over Magnesium sulfate and isolated by removing ether byrotary evaporation (1.3 gms). The product may be further purified bychromatography (silica 99% ethyl acetate/1% NH4OH at 5 ml/min.).Isolated yield: 0.78 g (mass spec, and H1 NMR)

[0567] The product from step 10 (0.57 gms, 1.02 millimole fw 558.83g/mole) and iodoethane (1.6 gms (10.02 mmol) was place in 5 mlacetonitrile in a Fischer-Porter bottle and heated to 45 C. for 3 days.The solution was evaporated to dryness and redissolved in 5 mls ofchloroform. Next ether was added to the chloroform solution and theresulting mixture was chilled. The desired product is isolated as aprecipitate 0.7272 gms. Mass spec M−I=587.9, ¹H NMR).

Biological Assays

[0568] The utility of the compounds of the present invention is shown bythe following assays. These assays are performed in vitro and in animalmodels essentially using a procedure recognized to show the utility ofthe present invention.

[0569] In Vitro Assay of Compounds that Inhibit IBAT-mediated Uptake of[¹⁴C]-Taurocholate (TC) in H14 Cells

[0570] Baby hamster kidney cells (BHK) transfected with the cDNA ofhuman IBAT (H14 cells) are seeded at 60,000 cells/well in 96 wellTop-Count tissue culture plates for assays run within in 24 hours ofseeding, 30,000 cells/well for assays run within 48 hours, and 10,000cells/well for assays run within 72 hours.

[0571] On the day of assay, the cell monolayer is gently washed oncewith 100 ml assay buffer (Dulbecco's Modified Eagle's medium with 4.5g/L glucose+0.2% (w/v) fatty acid free bovine serum albumin- (FAF)BSA).To each well 50 ml of a two-fold concentrate of test compound in assaybuffer is added along with 50 ml of 6 mM [¹⁴C]-taurocholate in assaybuffer (final concentration of 3 mM [¹⁴C]-taurocholate). The cellculture plates are incubated 2 hours at 37° C. prior to gently washingeach well twice with 100 ml 4° C. Dulbecco's phosphate-buffered saline(PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washedonce with 100 ml 4° C. PBS without (FAF)BSA. To each 200 ml of liquidscintillation counting fluid is added, the plates are heat sealed andshaken for 30 minutes at room temperature prior to measuring the amountof radioactivity in each well on a Packard Top-Count instrument.

[0572] In Vitro Assay of Compounds that Inhibit Uptake of [¹⁴C]-Alanine

[0573] The alanine uptake assay is performed in an identical fashion tothe taurocholate assay, with the exception that labeled alanine issubstituted for the labeled taurocholate.

[0574] In Vivo Assay of Compounds that Inhibit Rat Ileal Uptake of[¹⁴C]-Taurocholate into Bile

[0575] (See “Metabolism of 3a,7b-dihydroxy-7a-methyl-5b-cholanoic acidand 3a,7b-dihydroxy-7a-methyl-5b-cholanoic acid in hamsters” inBiochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.)

[0576] Male wistar rats (200-300 g) are anesthetized with inactin @100mg/kg. Bile ducts are cannulated with a 10″ length of PE10 tubing. Thesmall intestine is exposed and laid out on a gauze pad. A canulae (⅛″luer lock, tapered female adapter) is inserted at 12 cm from thejunction of the small intestine and the cecum. A slit is cut at 4 cmfrom this same junction (utilizing a 8 cm length of ileum). 20 ml ofwarm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flushout the intestine segment. The distal opening is cannulated with a 20 cmlength of silicone tubing (0.02″ I.D.×0.037″ O.D.). The proximalcannulae is hooked up to a peristaltic pump and the intestine is washedfor 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segmentis monitored continuously. At the start of the experiment, 2.0 ml ofcontrol sample ([¹⁴C]-taurocholate @ 0.05 mi/ml with 5 mM coldtaurocholate) is loaded into the gut segment with a 3 ml syringe andbile sample collection is begun. Control sample is infused at a rate of0.25 ml/min for 21 min. Bile samples fractions are collected every 3minute for the first 27 minutes of the procedure. After the 21 min ofsample infusion, the ileal loop is washed out with 20 ml of warm PBS(using a 30 ml syringe), and then the loop is washed out for 21 min withwarm PBS at 0.25 ml/min. A second perfusion is initiated as describedabove but this with test compound being administered as well (21 minadministration followed by 21 min of wash out) and bile sampled every 3min for the first 27 min. If necessary, a third perfusion is performedas above that typically contains the control sample.

[0577] Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL)

[0578] Liver tissue was weighed and homogenized in chloroform:methanol(2:1). After homogenization and centrifugation the supernatant wasseparated and dried under nitrogen. The residue was dissolved inisopropanol and the cholesterol content was measured enzymatically,using a combination of cholesterol oxidase and peroxidase, as describedby Allain, C. A., et al. (1974) Clin. Chem. 20, 470.

[0579] Measurement of Hepatic HMG CoA-Reductase Activity (HMG COA)

[0580] Hepatic microsomes were prepared by homogenizing liver samples ina phosphate/sucrose buffer, followed by centrifugal separation. Thefinal pelleted material was resuspended in buffer and an aliquot wasassayed for HMG CoA reductase activity by incubating for 60 minutes at37° C. in the presence of ¹⁴C-HMG-CoA (Dupont-NEN). The reaction wasstopped by adding 6N HCl followed by centrifugation. An aliquot of thesupernatant was separated, by thin-layer chromatography, and the spotcorresponding to the enzyme product was scraped off the plate, extractedand radioactivity was determined by scintillation counting. (Reference:Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).

[0581] Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI andVLDL+LDL)

[0582] Total serum cholesterol (SER.CHOL) was measured enzymaticallyusing a commercial kit from Wako Fine Chemicals (Richmond, Va.);Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) wasassayed using this same kit after precipitation of VLDL and LDL withSigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextransulfate method). Total serum triglycerides (blanked) (TGI) were assayedenzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B.VLDL and LDL (VLDL+LDL) cholesterol concentrations were calculated asthe difference between total and HDL cholesterol.

[0583] Measurement of Hepatic Cholesterol 7-a-Hydroxylase Activity(7a-OHase)

[0584] Hepatic microsomes were prepared by homogenizing liver samples ina phosphate/sucrose buffer, followed by centrifugal separation. Thefinal pelleted material was resuspended in buffer and an aliquot wasassayed for cholesterol 7-a-hydroxylase activity by incubating for 5minutes at 37° C. in the presence of NADPH. Following extraction intopetroleum ether, the organic solvent was evaporated and the residue wasdissolved in acetonitrile/methanol. The enzymatic product was separatedby injecting an aliquot of the extract onto a C₁₈ reversed phase HPLCcolumn and quantitating the eluted material using UV detection at 240nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084)

[0585] Measurement of Fecal Bile Acid Concentration (FBA)

[0586] Total fecal output from individually housed hamsters wascollected for 24 or 48 hours, dried under a stream of nitrogen,pulverized and weighed. Approximately 0.1 gram was weighed out andextracted into an organic solvent (butanol/water). Following separationand drying, the residue was dissolved in methanol and the amount of bileacid present was measured enzymatically using the 3a-hydroxysteroidsteroid dehydrogenase reaction with bile acids to reduce NAD.(Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).

[0587] [³]taurocholate Uptake in Rabbit Brush Border Membrane Vesicles(BBMV)

[0588] Rabbit Ileal brush border membranes were prepared from frozenileal mucosa by the calcium precipitation method describe by Malathi etal. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The methodfor measuring taurocholate was essentially as described by Kramer et al.(Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except theassay volume was 200 μl instead of 100 μl. Briefly, at room temperaturea 190 μl solution containing 2 μM [³H]-taurocholate (0.75 μCi), 20 Mtris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with10 μl of brush border membrane vesicles (60-120 μg protein). Theincubation was initiated by the addition of the BBMV while vortexing andthe reaction was stopped by the addition of 5 ml of ice cold buffer (20m Hepes-tris, 150 mM KCl) followed immediately by filtration through anylon filter (0.2 μm pore) and an additional 5 ml wash with stop buffer.

[0589] Acyl-CoA; Cholesterol Acyl Transferase (ACAT)

[0590] Hamster liver and rat intestinal microsomes were prepared fromtissue as described previously (Reference: (1980) J. Biol. Chem. 255,9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0ml incubation containing 24 μM Oleoyl-CoA (0.05 μCi) in a 50 mM sodiumphosphate, 2 μM DTT ph 7.4 buffer containing 0.25% BSA and 200 μg ofmicrosomal protein. The assay was initiated by the addition ofoleoyl-CoA. The reaction went for 5 min at 37° C. and was terminated bythe addition of 8.0 ml of chloroform/methanol (2:1). To the extractionwas added 125 μg of cholesterol oleate in chloroform methanol to act asa carrier and the organic and aqueous phases of the extraction wereseparated by centrifugation after thorough vortexing. The chloroformphase was taken to dryness and then spotted on a silica gel 60 TLC plateand developed in hexane/ethyl ether (9:1). The amount of cholesterolester formed was determined by measuring the amount of radioactivityincorporated into the cholesterol oleate spot on the TLC plate with aPackard instaimager.

[0591] Data from each of the noted compounds in the assays describedabove is as set forth in TABLES 5, 6, 7, and 8 as follows: TABLE 5 Invitro % Inhibition % Inhibition of TC of Alanine % of Control COM- IC50Uptake @ Uptake @ Transport of TC in POUND uM* 100 uM # 100 uM # RatIleum @ 0.1 mM # Benzothiaze 2  0 45.4 +/− 0.7 pine= 12 25  3 0  4a 3 5a 34  5b 40  0 72.9 ± 5.4 @ 0.5 mM  4b 9 18 6 14b 18 14a 13 13 23 1560 19a 0 19b 15  8a 41 Mixture of 69 8a and 8b Mixture of 6 9a and 9b 6a 5  6b 85  9a 5  0% @ 25 53.7 +/− 3.9 mM Mixture of 13 6a and 20Mixture of 0.8 14% @ 25 6d and 10a mM 21a 37 21c 52 21b 45  6c 2  58.568.8 +/− 5.7 at 0.4 mM  6d 0.6  77.7 16.1 +/− 1.1 @ 0.5 mM 30.2 +/− 0.9@ 0.15 mM 17 10  7 50  49.3 10a 7  77.6 62.4 =/− 2.5 @ 0.2 mM 10b 1568.6 25 0.1  4% @ 10 26.0 +/− 3.3 mM 26 2 31% @ 25 87.9 +/− 1.5 mM 27 5 7% @ 20 mM 28 8 31% @ 20 mM 29 88 @ 50 mM 30 96 @ 50 mM 31 41 @ 50 mM37 3  0% @ 5 mM 38 0.3 11% @ 5 20.6 +/− 5.7 mM 40 49 @ 50 mM 41 2  0% @20 mM 42 1.5 43 1.5 16% @ 25 mM 48 2 22% @ 20 mM 49 0.15 21% @ 200 21.2+/− 2.7 mM 57 51 @ 50 mM 58 20 @ 50 mM 59 70 60 9  59 61 30 175 62 10 6390 @ 6 mM 64 100 @ 6  mM

[0592] TABLE 6 TC-uptake TC-uptake TC-uptake ACAT ACAT (H14 cells) IlealLoop (BBMV) (liver) intestine Compound IC (50) EC (50) IC (50) IC (50)IC (50) COMP.   1 mM 74 mM   3 mM 20 mM 20 mM EXAMPLE 6d 0.6 mM 31 mM1.5 mM 25 mM 20 mM *38  0.3 mM 12 mM   2 mM 15 mM N.D. 49 0.1 mM 12 mMN.D.  6 mM N.D. 25 0.1 mM 20 mM 0.8 mM  8 mM  8 mM

[0593] Comparative Example is Example No. 1 in WO 93/16055 TABLE 7EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS 4% CHOLES- 0.2%PARAMETER CONTROL TYRAMINE CPD. NO. 25 WEIGHT (G) (mean ± SEM. *p<0.05,A-Student's t, B-Dunnett's) day 1 117 (2) 114 (6) 117 (5) day 14 127 (3)127 (3) 132 (4) LIVER WEIGHT (G) 5.4 (0.3) 4.9 (0.4) 5.8 (0.2) SER.CHOL(mg %) 143 (7) 119 (4) 126 (2) *A, B *A, B HDL-CHOL (mg %) 89 (4) 76 (3)*A, B 76 (1) *A, B VLDL + LDL 54 (7) 42 (3)*A 50 (3) TGI (mg %) 203 (32)190 (15) 175 (11) HEPATIC 2.5 (0.3) 1.9 (0.1) *A, B 1.9 (0.1) CHOL(mg/g) *A, B HMG COA 15.8 (7.6) 448.8 (21.6) 312.9 (37.5) (pm/mg/min.)*A, B *A, B 7a-OHase 235.3 (25.1) 357.2 (28.3) 291.0 (6.0) *A(pm/mg/min.) *A, B 24 HR. FECAL 2.3 (0.1) 2.7 (0.1) *A, B 2.4 (0.04) Wt(G) FBA 6.2 (0.8) 12.3 (1.5) 11.9 (0.5) (mM/24 H/100 g) *A, B *A, B

[0594] TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL20 MPL/DAY PARAMETER CONTROL CPD. NO. 25 WEIGHT (G) (mean ±SEM, *p<0.05, A-Student's t, B-Dunnett's) day 1 307 (4) 307 (3) day 8 330 (4)310 (4) *A, B LIVER WEIGHT (G) 15.5 (0.6) 14.6 (0.4) SER.CHOL (mg %) 85(3) 84 (3) HEPATIC CHOL (mg/g) 21 (0.03) 2.0 (0.03) HMG COA pm/mg/min75.1 (6.4) 318.0 (40.7) *A, B 7a-OHase (pm/mg/min) 281.9 (13.9) 535.2(35.7) *A, B 24 HR. FECAL WT (G) 5.8 (0.1) 5.7 (0.4) FBA (mM/24 H/100 g)17.9 (0.9) 39.1 (4.5) *A, B

[0595] Additional taurocholate uptake tests were conducted in thefollowing compounds listed in Table 9. TABLE 9 Biological Assay Data forSome Compounds of the Present Invention Human TC Alanine Uptake CompoundIC₅₀ Percent Inhibition Number (μM) @ μM 101   0 @ 1.0 102 0.083 103  13 @ 0.25 104 0.0056 105 0.6 106 0.8 107 14.0 @ 0.063 108 0.3 109  2.0@ 0.063 110 0.09 111 2.5 112 3.0 113 0.1 114 0.19 115 8.0 116 0.3 11712.0@ 0.625 118 0.4 119 1.3 120 34.0 @ 5.0 121 0.068 122 1.07 123 1.67124 14.0 @ 6.25 125 18.0 126   18 @ 1.25 127 0.55 128 0.7 129 0.035 1311.28 132  5.4 @ 0.063 133 16.0 134 0.3 135 22.0 136 0.09 137 2.4 138 3.0139 >25.0 142 0.5 143 0.03 144 0.053 262 0.07 263 0.7 264 0.2 265 2.0266 0.5 267 0.073 268 0.029 269 0.08 270 0.12 271 0.07 272 0.7 273 1.9274 0.18 275  5.0 @ 0.25 276 0.23 277 0.04 278 3.0 279 0.4 280 0.18 2810.019 282 0.021 283 0.35 284 0.08 286 19.0 287 4.0 288 10.0 @ 6.25 2890.23 290 0.054 291 0.6 292 0.046 293 1.9 294 0.013 295 1.3 296 1.6 10050.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.0011012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.002 10180.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 0.002 1024 0.0021025 0.002 1026 0.002 1027 0.002 1028 0.002 1029 0.002 1030 0.002 10310.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 1037 0.00221038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042 0.003 1043 0.003 10440.003 1045 0.003 1046 0.003 1047 0.003 1048 0.003 1049 0.003 1050 0.0031051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 10570.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.004 1063 0.0041064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004 10700.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043 10760.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.005 10820.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087 0.005 1088 0.00551089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093 0.006 1094 0.006 10950.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 11010.007 1102 0.007 1103 0.007 1104 0.007 1105 0.007 1106 0.0073 11070.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 1112 0.008 11130.009 1114 0.009 1115 0.0098 1116 0.0093 1117 0.01 1118 0.01 1119 0.011120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 1125 0.012 11260.013 1127 0.013 1128 0.017 1129 0.018 1130 0.018 1131 0.02 1132 0.021133 0.02 1134 0.02 1135 0.021 1136 0.021 1137 0.021 1138 0.022 11390.022 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.028 1145 0.0291146 0.029 1147 0.029 1148 0.03 1149 0.03 1150 0.03 1151 0.031 11520.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 0.04 1158 0.061159 0.06 1160 0.062 1161 0.063 1162 0.063 1163 0.09 1164 0.093 11650.11 1166 0.11 1167 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 11720.14 1173 0.15 1174 0.15 1175 0.17 1176 0.18 1177 0.18 1178 0.19 11790.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 1185 0.28 1186 0.31187 0.32 1188 0.35 1189 0.35 1190 0.55 1191 0.65 1192 1.0 1193 1.0 11941.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200 6.1 1201 8.3 120240.0 1203   0 @ 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 12080.042 1209   0 @ 0.063 1210 0.14 1211 0.28 1212 0.39 1213 1.7 1214 0.751215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 0.34 1220 0.2 1221 0.0411222 0.065 1223 0.28 1224 0.33 1225 0.12 1226 0.046 1227 0.25 1228 0.0381229 0.049 1230 0.062 1231 0.075 1232 1.2 1233 0.15 1234 0.067 12350.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 1241 0.047 12420.029 1243 0.63 1244 0.062 1245 0.32 1246 0.018 1247 0.017 1248 0.331249 10.2 1250 0.013 1251 0.62 1252 29. 1253 0.3 1254 0.85 1255 0.691256 0.011 1257 0.1 1258 0.12 1259 16.5 1260 0.012 1261 0.019 1262 0.031263 0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0.035 1269 0.0241270 0.024 1271 0.011 1272 0.047 1273 0.029 1274 0.028 1275 0.024 12760.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.055 1282 0.171283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 12890.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0.011 1295 0.0141296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1.0 1301 0.15 1302 1.41303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.04 1309 0.24 13101.16 1311 3.27 1312 5.0 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.01319 11.0 @ 0.25 1321 11.1 @ 5.0 1322  3.0 @ 0.0063 1323  4.0 @ 0.00631324 43.0 @ 0.0008 1325  1.0 @ 0.0063 1326 36.0 @ 0.0008 1327  3.0 @0.0063 1328 68.0 @ 0.0063 1329  2.0 @ 0.0063 1330  9.0 @ 0.0063 133157.0 @ 0.0008 1332 43.0 @ 0.0008 1333   0 @ 0.0063 1334 50.0 @ 0.00081335 38.0 @ 0.0008 1336 45.0 @ 0.0008 1337   0 @ 0.0063 1338  1.0 @ 0.251339   0 @ 0.063 1340  9.0 @ 0.063 1341  1.0 @ 0.063 1342  1.0 @ 0.0631345 13.0 @ 0.25 1347 0.0036 1351 0.44 1352 0.10 1353 0.0015 1354 0.0061355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 0.014 1360 0.003 13610.004 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.0021368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 13740.007 1375 0.002 1449 0.052 1450 0.039 1451 0.014

[0596] The examples herein can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0597] Novel compositions of the invention are further illustrated inattached Exhibits A and B.

[0598] The invention being thus described, it is apparent that the samecan be varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications and equivalents as would be obvious to one skilled inthe art are intended to be included within the scope of the followingclaims. TABLE C2 Alternative compounds #2 (Families F101-F123)

Family Cpd # R¹=R² R⁵ (R^(x))q F101 CHOSEN FROM Ph— CHOSEN FROM TABLE D*TABLE D F102 CHOSEN FROM p-F—Ph— CHOSEN FROM TABLE D TABLE D F103 CHOSENFROM m-F—Ph— CHOSEN FROM TABLE D TABLE D F104 CHOSEN FROM p-CH₃O—Ph—CHOSEN FROM TABLE D TABLE D F105 CHOSEN FROM m-CH₃O—Ph— CHOSEN FROMTABLE D TABLE D F106 CHOSEN FROM p-(CH₃)₂N—Ph— CHOSEN FROM TABLE D TABLED F107 CHOSEN FROM m-(CH₃)₂N—Ph— CHOSEN FROM TABLE D TABLE D F108 CHOSENFROM I⁻, p-(CH₃)₃—N⁺—Ph— CHOSEN FROM TABLE D TABLE D F109 CHOSEN FROMI⁻, m-(CH₃)₃—N⁺—Ph— CHOSEN FROM TABLE D TABLE D F110 CHOSEN FROM I⁻,p-(CH₃)₃—N⁺—CH₂CH₂— CHOSEN FROM TABLE D (OCH₂CH₂)₂—O—Ph— TABLE D F111CHOSEN FROM I⁻, m-(CH₃)₃—N⁺—CH₂CH₂— CHOSEN FROM TABLE D (OCH₂CH₂)₂—O—Ph—TABLE D F112 CHOSEN FROM I⁻, p-(N,N- CHOSEN FROM TABLE Ddimethylpiperazine)-(N′)- TABLE D CH₂—(OCH₂CH₂)₂—O—Ph— F113 CHOSEN FROMI⁻, m-(N,N- CHOSEN FROM TABLE D dimethylpiperazine)-(N′)- TABLE DCH₂—(OCH₂CH₂)₂—O—Ph— F114 CHOSEN FROM m-F—Ph— CHOSEN FROM TABLE Dp-CH₃O— TABLE D F115 CHOSEN FROM 3,4,dioxy-methylene-Ph— CHOSEN FROMTABLE D TABLE D F116 CHOSEN FROM m-F—Ph— CHOSEN FROM TABLE D p-F—Ph—TABLE D F117 CHOSEN FROM m-CH₃O— CHOSEN FROM TABLE D p-F—Ph— TABLE DF118 CHOSEN FROM 4-pyridine CHOSEN FROM TABLE D TABLE D F119 CHOSEN FROMN-methyl-4-pyridinium CHOSEN FROM TABLE D TABLE D F120 CHOSEN FROM3-pyridine CHOSEN FROM TABLE D TABLE D F121 CHOSEN FROMN-methyl-3-pyridinium CHOSEN FROM TABLE D TABLE D F122 CHOSEN FROM2-pyridine CHOSEN FROM TABLE D TABLE D F123 CHOSEN FROM p-CH₃O₂C—Ph—CHOSEN FROM TABLE D TABLE D

[0599]

What is claimed is:
 1. A composition, comprising an ileal bile acidtransport inhibitor and an HMG Co-A reductase inhibitor.
 2. Thecomposition of claim 1 wherein the HMG Co-A reductase inhibitor isselected from the group consisting of lovastatin, simvastatin,pravastatin and fluvastatin.
 3. A pharmaceutical composition,comprising: a first amount of an ileal bile acid transport inhibitor,and a second amount of an HMG Co-A reductase inhibitor, wherein saidfirst and second amounts of said inhibitors together comprise ananti-hyperlipidemic condition effective amount of said inhibitors, and apharmaceutically acceptable carrier.
 4. The pharmaceutical compositionof claim 3 wherein the HMG Co-A reductase inhibitor is selected from thegroup consisting of lovastatin, simvastatin, pravastatin andfluvastatin.
 5. A combination therapy method for the prophylaxis ortreatment of a hyperlipidemic condition in a mammal, comprising:administering to said patient a first amount of an ileal bile acidtransport inhibitor, and administering to said patient a second amountof an HMG Co-A reductase inhibitor, wherein said first and secondamounts of said inhibitors together comprise an anti-hyperlipidemiccondition effective amount of said inhibitors.
 6. The combinationtherapy method of claim 5 wherein the HMG Co-A reductase inhibitor isselected from the group consisting of lovastatin, simvastatin,pravastatin and fluvastatin.